ジェノト ロピン 2.6.2.5 薬力 学的薬 物相互 作用試験 Page1
August 25, 2009 August
and neither the drug theand neither drug
;
Ministry of Health, Labour and Welfare and Labour of Health, Ministry , 100 mg
he product is not classified as a biological biological a as classified is not product he
examination period is examination 8 years period -
the re
; ons were reached: t reached: were ons The PMDA shall not be responsible for any consequence resulting from l. Report on the Deliberation Results Deliberation the on Report Ono Pharmaceutical Co., Ltd. Co., Pharmaceutical Ono 100 mg 50 mg, 25 mg, Tablets Januvia Banyu Pharmaceutical Co., Ltd. Co., Pharmaceutical Banyu
(a) (a) (b) Glactiv Tablets 25 mg, 50 mg 25 mg, Tablets (b) Glactiv Sitagliptin Phosphate Hydrate (JAN*) Hydrate Phosphate Sitagliptin (a) December 10, 2007 December (b) Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Safety Food and Division, Pharmaceutical Licensing and Evaluation
.
proprietary name] proprietary - name] [Brand
substance nor the drug product is classified as a poisonous drug or a powerful drug. or a powerful drug a poisonous as is classified product drug the nor substance INN) (modified Name Accepted *Japanese use of this English version [Non [Applicant] [Date of[Date application] , the First Committee on New Drugs concluded that the product product the that concluded Drugs New on Committee First 24, 2009, the July held on the meeting In of Department Affairs the Pharmaceutical to presented be should result this that and approved be may Council. and Sanitation Food Affairs the Pharmaceutical of deliberation] [Results conclusi addition, thefollowing In product biological product or a specified This Englishconvenience versiontranslation, for of users.the the Japanese formerIn the shalleventreview prevai of report inconsistency is intended between to be thea referenceJapanese material original toand provide this English
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page2
e 25 mg,
2) July 8, 2009
monophosphat
Co., Ltd. Co.,
[1,2,4] one - - , equivalent to equivalent , 1
5H -
1) 2) tetrahydro Ono Pharmaceutical Ono 100 mg
100 mg 5,6,7,8- 1) 1)
2) , - ,
- trifluorophenyl)butan
Pharmaceuticals and Medical Devices Agency Devices Medical and Pharmaceuticals
,4,5- O 2 50 mg 50 mg (2 1) 2) , , ·H 4- Sitagliptin Phosphate Hydrate Phosphate Sitagliptin - 4 or registration are as follows. follows. as are registration or
yl] of Sitagliptin PO - 3 7 - 25 mg (trifluoromethyl)
Review Report Review - ·H O [3 - 5 1 N - None 6
F The PMDA shall not be responsible for any consequence resulting from
, or 100 mg a]pyrazin
15 l. H Amino 16 3- Each tablet contains tablet Each 50 mg - Banyu Pharmaceutical Co., Ltd. Co., Pharmaceutical Banyu Januvia Tablets Prescription drug (1) Drug with a new active ingredient active new with a (1) Drug drug Prescription Glactiv Tablets 25 mg Tablets Glactiv Office of New Drug I December 10, 2007 December 523.32 C Sitagliptin Phosphate Hydrate Phosphate Sitagliptin
)
R
.
(3
- triazolo[4,3 monohydrate
formula
Structural formula Structural Molecular weight name Chemical Molecular proprietary name] name] proprietary -
use of this English version [Application classification] [Application
on Agency Devices Medical and the Pharmaceuticals by conducted review regulatory a of results The f submitted product pharmaceutical following the [Applicant] [Reviewing office] [Reviewing This Englishconvenience versiontranslation, for of users.the the Japanese formerIn the shalleventreview prevai of report inconsistency is intended between to be thea referenceJapanese material original toand provide this English [Items warranting special mention] special warranting [Items [Chemical structure] [Chemical name] [Brand
[Date of[Date application] [Non [Dosage form/Strength] [Dosage
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page3
to 08 -
2) 5435 - the effect is is the effect July 8, 2009 July has concluded has concluded
If of the following of the following ONO
,
ardiovascular events events ardiovascular C P055
to any one any to , P054
1) 2) red once daily. exercise therapy exercise Ono Pharmaceutical Co., Ltd. Co., Pharmaceutical Ono 100 mg 100 mg exercise therapy exercise 1) 1) 2)
, , exercise therapy therapy exercise
/or 50 mg 50 mg
1)
2) , 3 , in phase III clinical studies etc. etc. studies clinical III phase in
therapy and /ortherapy marketing surveillance. surveillance. marketing - 25 mg Review Results Review
term use and the safety in patients with moderate renal renal moderate with patients in safety the and use term
- o dietary and/or therapy None identified
respond sufficiently do not who in patients e administ orally Sitagliptin of mg 50 in t addition Banyu Pharmaceutical Co., Ltd. Co., Pharmaceutical Banyu Januvia Tablets Glactiv Tablets 25 mg Tablets Glactiv December 10, 2007 December Sitagliptin Phosphate Hydrate Phosphate Sitagliptin
s have been been have
exercise therapy only therapy exercise
in to addition dietary
s /or in addition to dietary therapyto dietary in addition and
s he submitted data have demonstrated the efficacy and safety of the product in type type in product of the safety and efficacy the demonstrated have data submitted he
dosage is dosage
development etc. during long during etc. development
t, the dosage may be increased up to 100 mg once daily while closely observing the clinical clinical the observing while once closely daily 100 mg up to be increased may dosage the t,
Pharmaceuticals and Medical Devices Agency Devices Medical and Pharmaceuticals the review, regulatory its of lt
sual adult sual proprietary name] name] proprietary oncluded that t oncluded - tumor
10) etc. insufficien course. The u (b) Use of sulfonylurea of(b) Use
[Applicant] [Dosage and[Dosage administration] treatments. therapy Dietary (a) and thiazolidinedione of (c) Use [Indication] mellitus; diabetes 2 Type a resu As Sitagliptin be should only used problems safety No major name] [Brand
that the product may be approved for the following indication and dosage and administration. and administration. dosage and indication following the for be approved may product that the [Date of[Date application] [Non . mellitus 2 diabetes ( studies clinical III inphase shown has been product of the The efficacy of review] [Results c is It [Items warranting special mention] special warranting [Items -
and biguanide of(d) Use insufficiency need to be investigated via post via investigated to be need insufficiency
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page4
; the and
once
1 and/or - by 25 mg,
exercise exercise exercise s 2)
30, 2009
ered s have been been s have
and/or April and/or
hormone
in active form inactive
. in type mellitus diabetes 2 ncretin Pharmaceuticals and and by the Pharmaceuticals i
1) released 2) hate Hydrate, equivalent to equivalent Hydrate, hate therapy therapy in to addition dietary dependent insulinotropic polypeptide polypeptide dependent insulinotropic
- s Ono Pharmaceutical Co., Ltd. Co., Pharmaceutical Ono 100 mg
100 mg 1) 1)
2) lowers glucagon secretion from pancreatic pancreatic from secretion glucagon lowers , , agent
owing treatments owing 1 - rapidly inactivated by endogenous dipeptidyl endogenous by inactivated rapidly 50 mg of Sitagliptin orally administ of Sitagliptin orally 50 mg oll therapy therapy dietary to addition in exercise therapy only therapy exercise
in addition to dietary therapy s 50 mg GLP 50 mg
/or
1) s
2) , 4 , s are s are hyperglycemia prandial 1) and glucose - -
sensitizing sensitizing dependent action, thedependent action, cells. - of Sitagliptin - dosage is dosage
25 mg guanide
Review Report (1) Report Review 1 (GLP hormone -
When blood glucose concentrations are elevated, GLP elevated, are concentrations glucose blood When a new class of antidiabetic agents with a lower risk of of risk lower a with agents antidiabetic of class new a
.
None
the effect is insufficient, the dosage may be increased up to 100 to100 up increased be may the dosage is insufficient, the effect daily while closely observing the clinical course. clinical the observing closely while daily
If
sual adult sual
incretin therapy ingestion like peptide like
Improvement of post Improvement (d) Use of bi of Use (d) da ily. once mg who do not sufficiently do not inwho sufficiently patients only be used should Sitagliptin one of any to therespond f (b) Use of sulfonylurea of (b) Use therapy insulin of (c) Use (a) Dietary therapy Dietary (a) and Each tablet contains Sitagliptin Phosp Sitagliptin contains tablet Each 50 mg, or 100 mg 50 mg, exercise therapy exercise The u Banyu Pharmaceutical Co., Ltd. Co., Pharmaceutical Banyu Januvia Tablets Glactiv Tablets 25 mg Tablets Glactiv December 10, 2007 December Sitagliptin Phosphate Hydrate Phosphate Sitagliptin (PMDA)
meal
conditions in foreign countries etc. countries in foreign conditions usage and discovery of e to
ia. However, as the ia.However,
Due to their characteristic glucose their characteristic to Due in respons proprietary name] name] proprietary - increase insulin release from pancreatic β pancreatic from release insulin increase cells. cells. 1. Origin or history or 1. Origin Medical DevicesMedical Agency
[Applicant] attracting attention as the target of target the as attention attracting hypoglycem GIP α - glucagon including Incretins intestine II. Summary of the Submitted Data and the Outline of Review of Outline the and Data Submitted the of Summary II. hormones peptide are hormones, gastrointestinal which are (GIP), [Items warranting special mention] special warranting [Items [Proposed dosage and administration] and dosage [Proposed [Proposed indication] [Proposed I. Submitted Product Registration for name] [Brand
[Date of[Date application] [Non [Dosage form/Strength] [Dosage
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page5
, . : ) 4 4, - of - the
and have have No. No. et al., 1
S.p.A - DPP for the mg 100
thylene ) and then ” MF n B, n B, GLP D ** isa é ( ( disintegrant
outline of of outline Italia ,
20 ( reating type 2
in patients with with patients in and the and the ************* an , or 100 mg ( in , 2 25 mg 25 - and and inhibits DPP , vehicle
6879, Ahr , 50 mg PTP Inc. Co., & rodents and humans humans rodents and , 6 products submitted for for submitted 6 products The are in tablets supplied The proposed commercial The proposed commercial , confirmed
Sitagliptin igh density polye density high light beige (
of are unsuitable as a therapeutic as a therapeutic are unsuitable 80 countries/regions worldwide, Ono Pharmaceutical Co., Ltd. Co., at Pharmaceutical Ono trial trial Glactiv Tablet HDPE and Sitagliptin
- 6874 97: 2000; inhibitor is useful for t for useful is inhibitor 4 inhibitor in , these these ,
- tablets are are tablets , or Merck Sharp & Dohme & Sharp Merck
MF) by Merck 4 and edient of the -
D blister packages . *** ********* lives endogenous incretin hormones incretin endogenous - a clinical 50 mg rmaceutical Co., Ltd. Ltd. rmaceuticalCo., 25 mg , equivalent to 25 mg
the
contain by a DPP 5 , initiated initiated 1 - Whitehouse Station, N.J., U.S.A. N.J., Station, Whitehouse pink blister packages, blister ), the active ingr studies using a DPP has been approved in over approved been has GLP ) ************
Januvia Tablet the usefulness of the usefulness on Based . the Drug File ( Master
and is manufactured by by ismanufactured and
drug substance the drug containing tablets coated - s tablets are are tablets in
Sitagliptin ( Banyu Pharmaceutical Co., Ltd. Pharmaceutical Co., Banyu
Proc Natl Acad Sci USA Acad Natl Proc al., et
9, Sitagliptin 875). very shorthalf elimination
ppendix ations of the active forms of forms active the of ations
25 mg
marketing application for the product. product. the for application a marketing filed has applicant the , registered registered ) *************** Sitagliptin Phosphate Hydrate Phosphate Sitagliptin having
deficient mice and mice 4 deficient The -
before coating before cores the tablet is coating agent coating - Summary of biopharmaceutic studies and associated analytical methods analytical associated and studies of biopharmaceutic Summary tance 4), Marguet D, D, Marguet pertaining to the drug substance substance drug the of to summary the submitted pertaining data - (
developed by developed by
oduct - and (i) (i) A - 869 25: 2002; e
used during the clinical research stages and the bioequivalence between these these between bioequivalence the and stages research clinical the during used 4. DPP contains contains “
( 4 ee - ************************** s ( [
Summary the data submitted of
1 A study in study DPP ). A
, Inc. Co., & Merck by developed inhibitor thereby increasing concentr increasing thereby GIP active of stabilization the that suggested the and Europe. US including review are as shown in the A the in shown as are review tablets are beig are tablets PTP- ***** ************ The drug product consists of film consists product The drug pr (2)2.A. Drug 2. Data relating to quality relating 2. Data 2.A (1) subs2.A. Drug 200 as of April Japan, Outside The drug substance registration (the product) including including product) (the registration Ltd. solely Co., Japan, Pharmaceutical Banyu In co was the drug trials. clinical III phase of the stage lubricant, and film . free base Sitagliptin Hydrate Phosphate Sitagliptin peptidase drug. drug. diabetes mellitus diabetes ).220MF10082 Pha and Ono Ltd., PharmaceuticalCo., Banyu (Italy), bottles diabetes mellitus type 2 diabetes formulation formulations Diabetes Care, Diabetes
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page6
, , , , ), ed for for for for and and
total term sible , the
there - h ) s Step 3 , vi ” and - showed ,
and lux· under the the under tablets
*** ********
accelerat which both both which ing open system open ), the long , ************ and very slight
, and *** , and million million ultraviolet months months under the , ************** months ( ]
content uniformity 6 ) ********* stability of the drug of drug stability the individual ( months data at 1.2 (
***) ), 36
( ] NIR [ 36 blisters tablets] for each package package each for tablets]
,
lots of 100 mg the drug product has been product been has drug the 1 - Step 2 3 , term testing and accelerated accelerated and testing term storage storage HPLC - , ************** [ ), chemical ( stability studies on the tablets tablets the on studies stability
%RH . When the tablets packaged in in packaged tablets the When . PTP ****** 2 and 25 mg, 50 mg, and 50 mg, 25 mg, of each lots identification ambient humidity ambient -
/ *** , /65 , available been have 3 the ( term and accelerated testing accelerated and term ( C month month C
- and identification 25° 18 hereinafter referred to as “ toas referred hereinafter 30° 1 ( ( - ( , tablets
hardness. Disintegration test Disintegration hardness.
related substances related steps process critical as defined n term condition or for for conditionterm or , ckaged in ckaged blisters s condition ********, description 20**, ), ******************** pa 2 ( has been established. established. ) has been ******************* - Step 6 .
an overall illumination of illumination an overall 50 mg tablet tablet the long term and accelerated conditions and accelerated term long the ]
), were performed on the tablets packaged in HDPE inHDPE packaged tablets the on performed were in have bee have
content )
the drug productstored for attributes tested. Long tested. attributes 2 6 **, s
term testing term , As of * - lot of liquid chromatography liquid under
affect the physical and physical the affect . ( term testing and accelerated testing were performed on performed were testing accelerated and testing term ,
for ******* 1 , ************ on the results of an investigation in the manufacturing in manufacturing the an investigation ofresults on the - ·h/m (
************* . , ******* other ( long
aged in PTPaged , long by the accelerated accelerated the the tablets for blisters ,
Based and Step ** and Step 1 tablets description For Step at . -
Step 5
months themonths under long- *** ** ( , ************** . ),
slight decrease , and photostability testing , and photostability PTP 12 ) the tablets packaged in HDPE bottles in HDPE packaged tablets the
were s in specification the not included Though
lots of each strength [25 mg, 50 mg, 100 mg 50 mg, mg, [25 strength each lots of are 25 mg
≥
). Step microbial limits microbial were were (3 . *************** months
have been set been have ) **** 6 HPLC ( 1 lot 1 lot of disintegration, and water content. In long- In content. and water disintegration, there ). ( in water content content inwater ( , ]
but these changes do not changes these but , , blisters substances related purity, s ) storage bottles and bottles in have been set been have 1
for set been product have the drug for , ), -
NIR The attributes tested were the same as those for for those as same the were tested attributes The month storage data storage month s %RH ***** 6- ). ***************** PTP ( /75
and the proposed commercial formulation commercial the proposed and HDPE and assay and testing C ( assay [ assay the attributes tested theattributes ° , and dissolution and water content and There were no quality changes for changes quality no were There were observedalso for tablets 40 ),
( . stability studies of the drug product drug the of studies stability photometry ] blisters were stored for stored were blisters s for for Step 4
slight increase slight **, as, ********* term conditionterm , 1 ) and the ere consists of Step 1 of Step product for consists the process drug he manufacturing ***), HPLC type spectro bottles and in and bottles dissolution packaged in packaged ********, As The specification The tested *******, ************** ******************* product the for process development T ( 7 and Step Step formulations [ hardness of tablets was also tested. As a result a As tested. also was tablets of hardness an integrated near ultraviolet energy of 200 W energy ultraviolet near integrated an w lots scale commercial , lamp ultraviolet and near lamp fluorescent cool white condition testing showed no quality changes. Furthermore changes. quality no showed change PTP- product accelerated condition accelerated testing were performed on the tablets pack tablets the on performed were testing long- 100 mg very slight reductions in disintegration time time disintegration in reductions slight very
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page7
, s
the the ing
. at test
minutes
content and after
, in the final final the in ) blisters and and blisters
2 nd New Drug ing ************
. as indicated by by as indicated integration PTP- *************** seconds
, g that, demonstratin Also, with mg 100 dis , . ,
*** 3 years when stored in in stored when years 3 *** considering that if it can can it if that considering (
, month storage data data storage month of was performed using **, using performed was have been available, which which available, been have ****
As aresult, at *** 24- minutes) *** ********** also **% minutes
, ≥ Therefore h unacceptable bioavailability and bioavailability unacceptable h 20**, . condition ******* ****
rpm changes in manufacturing process etc. etc. process manufacturing in changes
***** dated May 1, 2001) May 568 dated to be included in specifications the
to
), or New Drug Substances a Substances Drug New or
*** ing . ***
exhibited on the tablets packaged in packaged the tablets on As of * The test attributes were description were The test attributes minutes) and a disintegration test showed also and a minutes) disintegration
s * ). ). ] ** ] distinguish
7 **** the accelerated the accelerated 36 months
% in tablets each tablets the applicant to include dissolution test dissolution include to applicant the . ********************
HPLC at blister packages at room temperature. temperature. room at packages 2 blister blisters [ - ** and 6
and a relationship between dissolution and disintegration disintegration and dissolution between relationship a and ( by can not not can 1 nience of operation in quality tests. quality in operation nience of
≥
-
term testing term
) - Basket Method Basket distinguish batches wit batches distinguish PTP (
*** to up interval second ing
*** /ELD Notification No. No. Notification /ELD ong rpm conve instructed ** SB
************************************* F nd Acceptance Criteria f Criteria Acceptance nd was at the P The l the final drug product product final drug in the willincluded be testing dissolution disintegration testing may be less discriminating as compared to as compared lessbe discriminating may testing disintegration ( . , ********** by minutes ” by PMDA in order to PMDA **
******** bottles and PTPbottles s ( month storage data storage month *****
uncoated tablets uncoated
6- individual and total and individual (
********* within and HDPE blister packages, or or packages, 1 blister ***********
- applicant to explain the relationship between dissolution and disintegration of the the of and disintegration between dissolution relationship the to explain applicant
showed rapid dissolution ( rapid dissolution showed *** ***** conditions ) and that
was , both ******************* , PTP
) s *** rpm
test
condition because bioavailability
asked the asked considers that disintegration test disintegration that considers m that that
Outline of the review bottles seconds ter
1) Dissolution coated tablets and tablets coated ( ***
Specifications: Test Procedures a Test Procedures Specifications: *** drug product and the reason for choosing disintegration test disintegration choosing for reason the product and drug was chosen taking also account of account also taking chosen was commercial scale lots will be continued up to up continued be will lots scale on commercial specification ********. Thethat responded applicant long- affecting dissolution be PMDA *********** , ************ ( A dissolution test of the drug product drug the dissolution test of A ********* **** of time disintegration mean (a rapid disintegration film- HDPE 2.B. PMDA follows: as responded The applicant 2.B is product drug the for life shelf proposed the results, above the Based on [ type package each substances related and both showed no quality changes no quality both showed has not been established etc. etc. established has been not specification product drug “ Substances Chemical Products: afterthe disintegration ofthe tablet, the drug is rapidly dissolved changes in formulation or manufacturing process affecting bioavailability process affecting or manufacturing formulation inchanges
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page8
, , s
the the end , **** the
sed by until ***
contents of of contents and within therange of
***************** . lied vely, at a commercial commercial a at tively,
as , the final drug product product final the drug uded in active ingredient ingredient active
rpm, respec rpm, Furthermore and the
***
tablets compressed tablets investigated. Asresult, a at a commercial ≥
*** . also tablets obtained from the beginning from obtained tablets
) *******
( 8 all
rpm and rpm %
s of ** ******************** from obtained ***
≥ that there are no particular problems with the specification the with problems particular no are there that
*** %to content . ******************
of tableting until tableting of **
test and
s
. during tableting was tableting during
. concluded . *****
beginning with . , ********************** ********************************* ****
PMDA active ingredient active egregation tent uniformity testing in the final drug product product finalthe drug in testing the uniformity to applicant include tent con was selected was S life for established the product drug
These test results test These results the - assured by blending at within the range within of
. and that and in order to distinguish changes in process parameters or manufacturing process affecting affecting process or manufacturing parameters in process changes to distinguish in order % s s lied was ********** niformity of dosage unit instructed . response the accepted mass variation test variation mass selecting for reason the to explain applicant the asked
sponse re the accepted 2) U (
mass variation test variation mass follows: as responded The applicant PMDA Based on the above, PMDA incl be will testing uniformity that content responded The applicant specification PMDA oftableting the from obtained tablets **% to *** ******** , and shelf storage When the blend uniformity in the blending and lubrication blending processes was asses was processes blending and lubrication in the blending uniformity the When blend uniformity 2.B. PMDA uniformity of dosage units of dosage the uniformity specification scale, production production scale. scale. production
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page9
,
, . . . 4 4 > - - and 12.9
DPP . platelet in vivo in 2.1 2.1 μM to 67 μM determined
, Inc. Co., & 22 derived from derived from of Sitagliptin and
enzymes, and and enzymes, quiescent cell cell quiescent
4 , 4 and - were 20.3, were - , which isabout 5.8 for other proteases , hemostasis Merck ) were ) were DPP QPP (
8.9 nM ofvalue 8.9 concentration
s, the effects on the the on effects the s,
II , values against DPP against values i
by μM K te i.e. selectivity
50
Sitagliptin was tested for for tested was Sitagliptin si , and dogs , and 4 , IC s - 10 μM s ion channels 100 values of values
human tissue was human and a i nnel nnel 4, >
- DPP The K
.
ice, rat cha + the DPP , m , and dog s 7.4 nM Na s
expression system expression ±
in the brain and were also expressed in in expressed also were and brain the in
receptors in receptors 0.9 is 0.9 inday) humans μM
annel, annel, 2A ice, rat 17.9 secretase, and and secretase, - mg/
ch
β
mainly of receptors with receptors , m ) 2+
) affinity and selectivity for DPP for selectivity and affinity
9 2A baculovirus
Ca As safety pharmacology studie pharmacology safety As values of Sitagliptin against various proteases were were proteases various against Sitagliptin of values
. [SD] 50 s human 5HT receptor. In a preliminary study a preliminary In receptor. type 4.2.1.1.1
- IC 2A L in vitro in 4 (
, -
in serum from4 in serum human maximum 100 - The assessed Sitagliptin inhibited the activity the activity of recombinant inhibited human Sitagliptin
ranzyme and B ranzyme . IKr human g . DPP 9, PEP (prolyl endopeptidase), APP (aminopeptidase P), and and P), (aminopeptidase APP endopeptidase), (prolyl 9, PEP 4. - DPP -
produced in the the of 5HT distribution been
for for and and , but the levels of expression in these tissues were lower than in the the in than lower were tissues these in expression of levels the but ,
4
- 2 from from in serum ve
receptor agonist activity was observed up to up observed was activity agonist receptor or higher μM
4 deviation standard . ha 8, DPP - receptors were expressed expressed were receptors 2A
the effects on the immune system and system immune the on effects the -
DPP
± , 50 μM
2A , respectively > DPP ) 4.2.1.1.1 ( 2 extracts and studies proteases, proteases, specific proline against of Sitagliptin values
- mean mean
), DPP ( and
umbilical vein umbilical 50 performed
value for the human 5HT human the for value proposed clinical dose ( dose clinical proposed IC 16.3 nM 16.3
4 inhibitors i - CACO value , secretase K
- the he electivity s and In vitro ) In γ 50 Primary pharmacodynamics T s were about 50 about were .1 , extracts
at values against ion channels ( channels ion against values 4 )
,
- dipeptidase 1 clinical data clinical 2 for for ( Summary submitted the data of 50
- -
max C IC fold the
other DPP Affinity for human and animal and human for Affinity Summary of pharmacology studies pharmacology of ) Summary DPP
i).A. i CACO Using human recombinant human Using the inhibitory activity against DPP against activity inhibitory the with an IC macrophage (b) derived from derived from proline respectively, but no rat 5HT rat no but respectively, As a result, human 5HT human result, a As
3.( (1)3.(i).A. (a) 3.(i).A studies, pharmacodynamic primary As 3. Non 3.( f glucose tolerance in various mouse models have been investigated. As secondary secondary As investigated. been have models mouse invarious tolerance of glucose improvement studies pharmacodynamic The applicant explainedThe applicant as follows: The Sitagliptin was screened for activity against proteases other than than other proteases against activity for screened was Sitagliptin . receptors 69.3, 52.4, and 10 μM prolidase 0.4- , U.S.A. N.J., Station, Whitehouse the inhibitory activity of Sitagliptin was competitive and reversible and competitive was Sitagliptin of activity inhibitory the vs. Sitagliptin bound to rat 5HT rat to bound Sitagliptin The respiratory system, cardiovascular system, central nervous system, renal function, function, renal system, nervous central system, cardiovascular system, respiratory pharmacodynamic drug interaction drug pharmacodynamic No assessed. been have function gastrointestinal and function, studies have been have studies
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page10
5 at in (
150 0.1, was in a ( , and
blood blood
about a a about . assessed load
90% in fasting in fasting , the 5 g/kg) about about
,
( the plasma the plasma
s
, excursion excursion . was ) 80% hyperglycemia, 700 nM challenged with with challenged
, glucose glucose a
about no change about
) obese (normal) mice mice (normal) obese inhibition of inhibition activity and increased increased and activity challenge the plasma Sitagliptin Sitagliptin plasma the
- of
after ere 4 , -
were treated with a single a with treated single were ) and then to be
55% .
tion was estimated to be estimated was mice ) 4.2.1.1.1
and develop obesity develop was inhibited by 68% inhibited by was
compared to the vehicle control control vehicle the to compared
) inhibi single oral dose of Sitagliptin of dose oral single
As there there w As . Therefore, Sitagliptin is unlikely to to unlikely is Sitagliptin Therefore, . 4 . mice ( ) - 46% ) per group 120 min induced blood glucose excursion glucose blood induced ) after a glucose challenge - 4.2.1.1.1 0- 8 mice] (
DPP glucose oral with challenged then and was estimated was methylcellulose
DIO ol group Plasma Sitagliptin concentrations increased increased concentrations Sitagliptin Plasma mice 4.2.2.3.7 n = 7- normal ( achieved achieved ,
. , respectively, , % 0.25 excursion excursion and then challenged with oral glucose oral with then challenged and sity
plasma plasma
excursion glucose blood were treated with a single oral dose of Sitagliptin of dose oral single a with treated were ( )
at a dose of 1 mg/kg of dose at a mice[ glucose a glucose after minutes at 20 10 the applicant explained that Sitagliptin is considered considered is Sitagliptin that explained applicant the
) obese ( obese , - groups max 4.2.2.3.2
3 mg/kg receptor in a clinical setting clinical in a receptor t ( dose ( 2A dose - As a result, glucose result, a As - compared to the control group, and a plasma Sitagliptin Sitagliptin a plasma and group, to control the compared ) methylcellulose maximal efficacy in inhibiting blood glucose blood inhibiting in efficacy maximal Sitagliptin inhibited plasma DPP plasma inhibited Sitagliptin and .
t a dose of 3 mg/kg of t a dose blood glucose tolerance in of response blood to ament glucose nduced obe nduced ) group per ) or vehicle , 1 mg/kg 1 i dose % - - a the ratio of brain to plasma concentration of Sitagliptin was ≤ was of Sitagliptin concentration toplasma of brain the ratio -
) in oral glucose tolerance test in non in test tolerance glucose oral in , dose 28
- iet methylcellulose dependent manner Based on the results of a mouse pharmacokinetic study pharmacokinetic a mouse of results the on Based max 0.25
compared to contr the compared post - ( . , Induced Obesity Induced % mice fasted overnight fasted mice - achieving
tin on blood glucose on blood tin glucose
hour hour n = 20- tic study tic Sitagliptin resulted in resulted Sitagliptin , and 30 3, and As a result ( dose (t
0.25 human 5HTthe human
Diet - ( DIO , 3, 30 mg/kg , . ( evaluation at 80 minutes post 80 minutes at 1 hour 1 post
0.3 in a dose 0.3 or vehicle ( 3 mg/kg dose at - Male ) 1 studies t -
, respectively , . distribution theinto distribution brain ( A
diet fat As a result, Sitagliptin inhibited inhibited Sitagliptin a result, As - . . or vehicle vehicle or
) mice mg/kg 120 min igh
at 1 hour post 2 g/kg) 0- 3 glucose tolerance in d in tolerance glucose Sitagliptin Sitagliptin dose In vivo ) In -
, the effect of Sitaglip ance test in non in test ance toler glucose oral in 1 .2 1 hour post mg/kg Based on the results of a pharmacokinetic study in study DIO of results Based a on the pharmacokinetic 3 In a ratpharmacokine In at a active GLP a active in the 0.3, dependently dependent manner and Sitagliptin Sitagliptin and manner dependent
- - 1, ) Pharmacodynamic .
Effect Effect agliptin concentration 1 at concentration agliptin Effect on Effect hour post fold increase in plasma active GLP active inplasma foldincrease ) 4.2.1.1.1 0.1, nM (b) ( overnight fasted mice Male ( . group concentration concentration (a) (1)3.(i).A. a with treated were group) per 7 (n= overnight fasted mice Male 0.3, Sit As mice fedh mice As impair have and hyperinsulinemia and , challenge (c)
using theusing DIO
brain. , indicating low 0.1, indicating via effect aexert significant 82% blood glucose from baseline at 1 hour post hour 1 at baseline from bloodglucose not to affect fasting notblood fasting glucose to affect inhibited by Sitagliptin atAUC Sitagliptin and the all doses glucose inhibited by blood oral dose of Sitagliptin of dose oral oral ( glucose g/kg plasm dose 1 dose 3- oral glucose tolerance test, test, tolerance oral glucose concentration of 600 nM of concentration glucose AUC glucose
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page11
, , ; ; in cell cell was was -
db/db T values values
Ile thia Ile - reduced mg/day 3, 10, 30 50
Diabetes values of of values
( the effects the effects ,
allo 50 duced in the mixed , respectively cell activation in - IC - et al. et 375),
2 ) and - the Sitagliptin does not not does Sitagliptin IL significantly , ), 100 μM normalized to normal to normalized normal
maximum 100 maximum or > (
production has been suggested to be tobe suggested been has 4 clinical studies, including including studies, clinical -
- 2 inhibition. Thus, selectivity inhibition. Thus, selectivity - at a dose of 3 mg/kg at a dose Lankas GR, GR, Lankas 8.9 nM , and ( inhibition ofT inhibition ( 9
) - IL 1999; 1999; 20: 367- 4 , - CD26 max 100 , respectively, and the IC and the respectively, ,
t ( DPP and .
DPP μM or isoleucyl thiazolidine isoleucyl -
8 14 for for ucose was nearly was ucose cells dose - . - inhibiting DPP inhibiting
Sitagliptin at all doses all at Sitagliptin 2S,3S DPP , and -
) 4.2.1.1.1 value value ,
dependent immune response were evaluated evaluated were response immune dependent Immunol Today Immunol ( - 1.6 ) 4 ., Ki - ,
threo - acetate myristate phorbol cell - 11 , 48, > were 0.018 P
2.2 cell proliferation cell L et al - ( , respectively B
T or lowering effect of Sitagliptin was investigated in investigated was Sitagliptin of effect lowering 4.2.1.1.1 As As a result ) 4.2.1.1.1 -
Based on the results of a pharmacokinetic study in db/db study a pharmacokinetic of results the on Based
( - inhibitors was assessed. As a result As assessed. was inhibitors ( . ). e thia cell activation antigen and antigen activation cell 18 μM in vitro in for Sitagliptin of value 4 Il
- 9, and QP cell - T 50 were 0.42, dose
T - a are known to produce to known are toxicity in non IC induced proliferation of B induced proliferation , - hreo- , t ) on De Meester I, I, Meester De
( he
) fold the higher than 8, DPP
- Ile thia Ile were treated with a single oral dose of Sitagliptin of dose oral single a with treated ) were 8 per group - . - CD26
μM
multiple organ histopathology, and mortality histopathology, organ multiple cell activation , hours post hours he blood glucose he methylcellulose to other DPP to , 0.32, and 0.22 B 50
hreo
n = 7 4 4, DPP t - % . T ( are related to are related these toxicities and immunity to
at studies
0.5 Sitagliptin did not inhibit inhibit not did Sitagliptin , cell and 2994)
- 1000 than more
12 nM compared values of values T were 0.46, were
( is identical to to identical is inhibitors, including inhibitors, including ). 50 isoleucyl thiazolidine isoleucyl In vitro ) In 4 4 - was mouse is a murine model of type 2 diabetes characterized by severe insulin resistance and and resistance insulin severe by characterized diabetes 2 type of model murine is a mouse - - 2988- to be 400 nM about .1 micee db/db )
Secondary pharmacodynamics ) Secondary (db/+ mice) (db/+ 2 or vehicle ( or vehicle
Ile thia Ile
s the plasma Sitagliptin concentration at 1 hour post at 1 hour concentration Sitagliptin the plasma DPP - DPP ) As As a result 2S,3R ffect in mice db/db onblood glucose , db/db . , 0.9 μM - E Selectivity of comparator compounds for DPPfor compounds Selectivity comparator of 50 μM Effects on on Effects
allo max > allo cause immunosuppression also at the proposed clinical dose clinical proposed the at also immunosuppression cause C , orproliferation lipopolysaccharide Sitagliptin against DPP against Sitagliptin
t as that explained Theapplicant of (d) ( Other ( anemia thrombocytopenia, 2005; 54: (b) , antigen to response in or reaction lymphocyte estimated estimated while the IC the while
The marked hyperglycemia Mal mice. of Sitagliptin Sitagliptin of ( 3.(i).A. (2)3.(i).A. (a) mg/kg vitro Since Since of Sitagliptin control mice compared to the vehicle control and blood gl blood and control vehicle the to compared glucose blood protective in protective involved
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page12
,
, ) ) s ] 10 ere and , was was μM SE w 2
[ n = 6
) ( related ) at - current
resolved 117
50 mg/kg 50 and and therewere no channels channels
liptin yielding yielding liptin 10,
,
hERG which , 2, related effects on on effects related 147 ( -
standard error standard
hERG dose ) - ± rats male onscious 33.9 33.9 μM , and 6.89 As a result a . As
values of values
mean mean
( 50 in rats (5 males and 5 females females 5 and males (5 inrats 4.2.1.3.5 As a result, there were no interval corrected for heart rate heart for corrected interval
there were no treatment no were there
) ( minute ventilation, Penh ventilation, minute the effects on the cardiovascular cardiovascular the on effects the IC , responses activity stimulus ). , QT
Sitagliptin inhibited inhibited Sitagliptin heart rate, ECG parameters ECG rate, heart at 4 hours post hours 4 at ,
or . reversible almost was
, 1.60 was dose there no treatment were doses and - 180 mg/kg 180
,
60, interval, interval, beats/min
minute period, minute tidal volume tidal , . As a result As 9 the mean heart rate rate heart mean the .
) 4.2.1.3.1 , the effect of Sitagliptin on Sitagliptin of effect the
20 ,
QT ± 10
(
(
,
12 ) , observations field 10 mg/kg
As a result As , pressure arterial dose 127 (
. and occurred with a concomitant slight shortening of the of PR shortening slight with a concomitant occurred no important changes in blood pressure, heart rate, blood blood rate, heart pressure, blood in changes important no were given an intravenous infusion of Sitag an infusion intravenous given were over a over , 2 interval recordings
, channels
were given single oral doses of Sitagliptin of doses oral single given were 4.2.1.3.2
) 4.2.1.3.4 ( dose study dose ( of Sitagliptin (20, 60, 180 mg/kg) in c mg/kg) 60, 180 (20, Sitagliptin of ) 4.2.1.3.3 QRS 50 mg/kg 50
( respiratory rate respiratory
ERG ) females ( clamp - 30 mg/kg evaluation on hERG Sitagliptin of 2 held,- and open
at baseline to to baseline at tachycardia As a result As ,
. ogy
, and, interval the at interval The hand- /min
male After the the After . . . 10 function 1 All dogs received all doses in a crossover fashion in crossover a doses all received dogs . All PR
3, cell voltage cell beats dose - ,
- up and supplemental studies safetyand pharmacology up function cardiovascular 1 5 -
, pressure arterial
) females 2 and males ± 2 cells expressing h expressing cells ( s formula
foot splay, and body temperature measurements temperature and body splay, foot ’ 94 , cage home battery core pharmacology afety , , respectively respiratory Follow K1 The inhibitory activity of Sitagliptin against hERG against Sitagliptin of activity inhibitory The were assessed by a functional observational observational functional a by assessed were system nervous central the on effects the electrophysiological - ) ) S . heart rate or , hours post hours ,
the mean the mean using whole body plethysmography body whole using ts on the central nervous system nervous the central on ts effec related .2 .1
- effects on effects Safety pharmacol ) Safety HO 3
ular by a step voltage protocol and a ramp voltage protocol with nesthetized dogs ( dogs nesthetized The plasma Sitagliptin concentration at 1 hour post hour 1 at concentration Sitagliptin . The plasma ed
C Fridericia the Cell Effects on respiratory function respiratory on Effects Cardiovascular effects: Cardiovascular escalating Effects on cardiovascular function cardiovascular on Effects evaluat respectively (c) Conscious dogs dogs Conscious (3)3.(i).A. When a cumulative doses of doses cumulative assessed were ECG and system system nervous central on (d) Effects Following single oral administration oral single Following Sitagliptin of administration oral single Following ) per group (b) (3)3.(i).A. (a) ( 3.(i).A. respiratory function. grip strength treatment (a) Using whole by investigated battery assay ( assay battery per group) and evoked at 6 about interval evaluated using telemetry using evaluated changes in changes and 50 mg/kg using using d from d from increase effects on
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page13
. 3 n = and dog dog was The ( lung lung As a n = There . 1 ) , ( , . minutes minutes 460) was 58.7 was potassium increase in in increase 15
of 453- O/L/sec
2 but the change noted and the and the noted . 10 mg/kg SE) at 5 22:
10 mg/kg within within ±
ere At ) at noted
w
.
Concerning effects on on effects Concerning
A transient decrease in in decrease transient A . s max ). 2.83 cmH 2.83 was ( C
resolved SD , respectively 4.2.1.3.1
there was a 65% was there ( ± intrapulmonary pressure intrapulmonary were seen were dose , -
al range for dogs of average size size of average dogs for al range and blood pressure and heart rate rate heart and pressure blood and no supplementation no
. No output acid gastric stimulated
physiologically meaningful physiologically -
dose, , respectively mean mean - concentration ( plasma electrolyte concentrations, and and concentrations, electrolyte plasma
norm trin
function , dogs showed a moderate decrease in in decrease moderate a showed dogs
and the mean and the mean to 9.46 μM J Appl Physiol,; 1967
which dogs,
its 262 μM 2 ) 4.2.1.3.1 or gas to 0.24 μM 0.24
( O/L/sec hour post 2 ±
expiratory flow expiratory 1
130
. because because 8.7
Stahl WR, WR, Stahl due to very low airway resistance values at baseline baseline at values resistance airway low tovery due ion and 2 ion 13 dogs female toconscious administered ) was ( At
but there were no changes in other ECG parameters parameters ECG other in changes no were there but , and platelet . ) , 0 and 2.59 cmH determined not to be determined
excret clinical observations s in clinical
4. 1, 3, and10 mg/kg ±
electrolyte excretion electrolyte . 7.4% were seen were in plasma potassium plasma in , ± O/L/sec 10 mg/kg 2 at
dogs male anesthetized to administered was Sitagliptin of
4.2.1.3.1 3.05 ( The plasma Sitagliptin concentrations (mean (mean concentrations Sitagliptin plasma The
, there were no effects on renal function, including glomerular glomerular including function, renal on , there effects were no , hemostasis and . interval
ere 1 of Sitagliptin was administered to conscious female dogs (n = 6) = (n dogs female conscious to administered was of Sitagliptin increased increased 3.7 cmH 3.7 , which was
QTc 10 mg/kg . changed meaningfully not were gases and blood in heart rate were observed in heart rate in observed were to
1 mg/kg was within the range of range the within was
dose were 37.8 were dose - max s decrease light interval interval S
10 mg/kg observationsclinical
corrected corrected increase in potassium increase increase - PR
, the C Sitagliptin had no effects on peak had no effects Sitagliptin 8.69 and 0.576 to 0.634 was mg/kg 1 and 10 , the gastric acid secretion at effective renal plasma flow plasma renal effective hour post 1 hour activated partial thromboplastin time thromboplastin partial activated in reduction significant tidal volume, and respiration rate and respiration tidal volume, , As a result, at a result, As a max electrolyte excretion function and electrolyte on renal . excretion , seconds on average seconds and changes in changes
C ECG parameters were observed were parameters ECG 30 mg/kg
1.5 gastric acid secretion acid gastric on effect no had Sitagliptin
or , At dose and ≤ . The -
As a result As . Effects Effects Effects on on Effects Effects on respiratory function respiratory on Effects airway resistance and the applicant discussed that that discussed the applicant and resistance airway . change percent a high in resulted value resistance airway the in increase slight a even dogs, in 2 post athour 1 observed value resistance airway maximum mean result compliance emesis or emesis A single oral dose of dose oral single A
flow, μM the laboratory background data the laboratory background w has been reported to be 0.6 be to reported been has of little toxicological significance toxicological little be of to considered (c) A single intravenous of dose intravenous single A
decreased decreased blood pressure bloodpressure and 3). including heart rate including (b) The mean arterial blood pH blood arterial The mean , hemostasis was ions ). per group filtration rate A single oral dose of Sitagliptin ( Sitagliptin of dose oral single A orchange no emesis fraction, and filtration slight a exhibited applicant discussed that this finding is likely to be associated with with associated be to likely is finding this that discussed applicant potassium were no effects on platelet function on platelet were no effects post (d)
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page14
is the 4 , - 1999; 1999; T cellT P
). As a
glucose glucose induced induced molecule molecule has been been has the
during the the during
on various
erefore 4 - n = 10
Th 4 - . after a et al., Proc Natl Natl et al., Proc
DPP knockout mice have mice knockout fertile
are present ma concentrations of of concentrations ma
4 The phenotypic change change The phenotypic - 6830). . also 4, including the active site, 4, including the site, active - behavior, motor activity, or activity, motor behavior, et al., Immunol Today, et Immunol al., Marguet D, D, Marguet (
clinical observations clinical ) 4.2.1.3.1 ( 4 and CD26 hormones - and drug obesity induced - - cell activation assays suggested that that suggested assays activation cell - , function and lower plas and lower triggered by the ligation of ligation the by triggered physiological role has been elucidated elucidated has been role physiological T
ut mice is considered to be the major major the be to considered is ut mice DPP
2003; 100: 6825- 2003; 100: the function blood glucose excursions glucose blood type animals, DPP animals, type De Meester I, I, Meester De there is no definite evidence that DP that evidence definite no is there normally and are , (
, n vitro knocko lacking the gene encoding DPP encoding gene the lacking I
s 4 .
-
and insulin and major histocompatibility complex (MHC) complex histocompatibility major 14 - specific signal signal specific However 1 1 and GIP, incretin GIP, 1 and - - - are resistant to arediet resistant . animal
receptor improved tolerance glucose improved
GLP ptin was administered to conscious female mice (n = 10). As As 10). = (n mice female conscious to administered was ptin ompared to wild- to ompared ) 4.2.1.3.1 antigen ( be multifunctional C USA, Acad Sci atl of GLP
ost of the extracellular part of DPP part of the of extracellular ost
oint of
M ell activation antigen and and antigen ell activation ies . c eptide antigen eptide - observed in DPP
p T
develop mice 4 knockout 6879). of Sitagli of stimulatory by PMDA - c asked the applicant to discuss the potential for Sitagliptin to affect toaffect Sitagliptin for the potential discuss to the applicant asked
- knockout mice mice knockout
4. , a - co 4 invivo functions other than the regulation of incretin activity, of which its its which of activity, incretin of regulation the than other functions
-
a challenge, resulting in reduced reduced in resulting challenge, stimulatory receptor stimulatory
- mg/kg DPP specifi et al., Proc N al.,et Proc CD26 PMDA 0 DPP and DPP from the viewp , , the from 10
( mice female conscious to 10 mg/kg administered was of Sitagliptin several
deficient animals is the is animals deficient
by 4 has been suggested to suggested been has - 2000; 6874- 97: 2000; 4 However, there is no definite evidence that the immune function etc. are altered in etc. function altered are immune that the evidence no definite there is However, - have
cell activation activation cell - cell activation requires an requires cell activation - T In addition, In DPP Conarello SL, SL, Conarello , central nervous system nervous on central effect no had Sitagliptin ( Discussion ) Discussion Effects on the immune function function immune on the ) Effects Outline of the review complex complex 375). is identical to identical 4 is
- 1 2 d in DPP , may serve as a co a as serve may knockout mice knockout affect did not and affect transit on intestinal had no effect Sitagliptin second signal second
, 4 4 a - - minute exposureminute period. Effects on gastrointestinal motility motility gastrointestinal on Effects central nervous system system nervous central other and behavior on Effects
sult re 80- A single oral dose of dose singleoral A . thermoregulation 3.(i).B cells in body etc. the . cells various The applicant responded as follows: follows: as responded The applicant As DPP ( 3.(i).B. (f) (e) a result Although Although A single oral dose of dose single oral A only for the activit regulation of the observe receptor receptor and DPP USA, Acad Sci of active concentrations plasma higher Generally physiological function of function physiological ( 3.(i).B. 20: 367- as activity incretin of regulation glucagon after a glucose a glucose after glucagon diabetes to suggested . challenge DPP involved in T involvement in the immune function is of greatest interest greatest of is function immune in the involvement
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page15
,
, , s 8 - of
cell and lack - were
. 8 s et al. et - 9 Lankas - (
R, involved. decreases secretion, secretion, 2000; 72: 72: 2000;
promising promising
et al., Clin DPP β is DPP - regardless regardless 4 , - s in the immune in immune the cell lymphoma highly selective selective highly a study done by done by a study functions except except functions and - TGF
the expression of the of expression an increase in the inthe increase an 4 a 4 or inhibition of its its of or inhibition 8 - dies were found to to found were dies , Lankas G Lankas DPP - elective / increases - , ( , Inc. Co., & Merck gs on immunegs cells 4
) in T - stimulation in T in stimulation of
- of melanoma cell line cell melanoma of , cells DPP DPP , , etc. DPP
in vitro in Pethiyagoda CL, noma mela transformed
( according to
induction of of induction tumor tumor
, , For example et al., Immunol Lett, Immunol al., et As a result, s a As result, Furthermore 301). lck active site site active .
. basal cell carcinoma, and breast breast and carcinoma, cell basal , p56 in vitro /FAPseprase , of ness invasive the However enzymatic activity is not important for for important not is activity enzymatic
in vitro Hühn J, Hühn in vitro in dependent immune response in mice in response dependentimmune 4
- ed - 8). an involvement of DPP involvement an , ite reversibly site active in vitro Changes in the expression of these peptidases of these peptidases inthe expression Changes cell proliferation invasive activity invasive selective inhibitors of inhibitors selective - 113 - 4 2008; 29: 295- other thethan genetic deficiency of deficiency genetic - , - these drugs showed showed these drugs as that discussed been has it
5). inhibit In order to investigate the involvement of DPP involvement the order investigate In to may transduce proliferative signal proliferative transduce may assessed assessed a recent study a recentconducted by study
presenting cells has been identified as a as identified been has cells presenting thyroid cancer CD13/APN, 4
or B cell or B 4 - site , 9. that - 15 -
1133 - the study results were interpreted differently interpreted were results study the ere
a , inhibitors DPP cell cell activation cell DPP Especially, the drugs used in these stu these in used the drugs Especially, 4 - DPP c activity is not essential for co for essential not is activity c T - , Indeed demonstrated the effects of these of these dru the effects demonstrated So far, there have been no reported data reported suggestingno been have there that far, So T derived shown - . that that ggesting that DPP hyperphosphorylation hyperphosphorylation on antigen- and stimulatory activity ( activity stimulatory
- CD10/NEP 1 su 8 inhibition - 2002; 383: 2002; 2994). - 1999; 190: 190: 301- 1999; 4,
studies and studies , 4 - , U.S.A. N.J., ion, - enzymati has also also has
4 tivationcell ac w 400), - et al., Trends Immunol, Trends et al., - DPP , production in vitro in vitro , suggesting
o malignant transformation has been demonstrated transformation o malignant DPP was not required for its anti its for required not was as selective DPP selective as
Sitagliptin binds to the DPP the to binds Sitagliptin 2994). Biol Chem Biol J Exp J Exp Med,
CD26/DPP shown to have no effect on T , (
if will notbe altered no apparent effect on no apparent effect . cells and tissue of the types on depending vary s
that that
expression is seen in melanocytes in melanocytes isseen expression
4, but also DPP - 54: 2988 2005; s
-
, 4 due t was 4 Ohnuma K, Ohnuma Whitehouse Stat Whitehouse - - Constitutive expression of of expression Constitutive et al. et invasion and metastasesinvasion on T cells on T 4
2000; 18: 391- 18: 2000; - DPP ty ha
observed in 4
- DPP as in immune cells reported with these drugs these with reported cells in immune Diabetes indicating DPP hile hile ,
9 ) Tumor ectopeptidase - 2005; 54: 2988- , 2005; 3 W enzymatic activity enzymatic inhibitors were found to attenuate attenuate to found were inhibitors for
, cell, leukaemia lymphocytic acute .
9 . 4 expression et al. et - - 132), specific effects other than than other effects specific DPP the Reinhold D, D, ) (Reinhold
cell cell - , cytokine inhibition growth C, Morimoto & S Iwata ) decrease or increase 127- etc. Co., , & Inc. Merck non- GR,
categorized drugs Using co its affecting without deleted be can inhibit notinhibit only proliferation proliferation function has has beeninvestigated, which ( and synthesized and the effects on T effects and the synthesized DPP DPP of inhibitor expression of DPP expression T ( ( According to a recent report, caveolin report, toa recent According ligand cancer multiple multiple It has been confirmed that when normal cells transform into malignant transform cells normal when that confirmed has been It ( 3.(i).B. Diabetes but for enzymatic activity enzymatic for DPP U.S.A. N.J., Station, Whitehouse enzymatic activity ( activity enzymatic even that is expected It Exp Metastasis, enzymatic activi enzymatic . of melanocytes transformation malignant
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page16
, . in of no for for for the
4 - 4, e.g. even if if even - from its its from substrate
Proc Natl shown assays assays ct
will not be ,
cleavage degradation DPP
by DPP
the binding of theof binding
by distin is well tolerated well is in vitro in 4 knockout mice 4 knockout
- , Therefore is n vitro I Cheng HC, et al., HC, J Cheng growth growth e.g. family, ( 4 -
fibronectin regulated .
an adhesion receptor receptor an adhesion to in vitro their putative putative their
24215). . in DPP .
4 also inhibition related changes in peptide inpeptide changes related - as
etc 4 glucagon - . substrates are Conarello SL, et al. SL, Conarello have no effect on effect no have clinical studies have have studies clinical
DPP
4
- . , other peptidases are involved in in involved are peptidases other 4, - DPP of tumor invasion and metastases and and metastases and invasion tumor and stimulates the release of growth growth of release the stimulates and
s serves fertility fertility inhibition- 6879, DPP
DPP times the exposure at the clinical dose at the clinical the exposure times 1/GIP Due to the lack of suitable of lack the to Due 4 in vivo - s of the - s peptide bioactive . substrates substrates s 58 - 6874 binding 4 in vitro in -
> - 1998; 273: 24207 the applicant fully assessed fully theapplicant GLP DPP binding domain of DPP domain binding
4 in vitro in related to related
, - , s the DPP ,
are
with with DPP 16 metastases metastases have been shown to been to shown have
/ Chem
2, endothelial cell
in addition toin addition chemokine - s 2000; 97: 2000; , by e, suggesting that suggesting e,
, However in vivo in on tumor invasion and metastases and invasion tumor in vitro in . these peptides or proteins and or proteins peptides these fibronectin . Even 4 and at exposure at - 4 bioactive peptide bioactive J Biol
fertil - , of s
the ., several protein protein that several recognized isit generally and proteins
DPP metastases incancer is involved and cells DPP substrates to be closely examined based on based examined closely be to substrates important most efficiently 6830). some some studies
Furthermore levels ,
. 24215), most enzymatic activity is un is activity enzymatic GIP GHRH) and GLP tumor development tumor ( ed that that ed
4 neuropeptide selected - clinical , and family peptides family then discussed as follows. as discussed then serine protease inhibitor protease serine - Cheng HC, et al DPP and 1 ( d cleave - endogenous
Proc Natl Acad Sci USA Sci Acad Natl Proc 4 - , mice are healthy and healthy are mice - 6825 100: 2003; the of these peptides or of these
GLP
no serious effects on development or development on thereeffects serious are no , lucagon bioactivity as well theiralters bioactivity DPP , has report has been 4 activity affects 4 activity - 24207 273: 1998; - ) G
cancer ofcancer surface on the
of except non- except for should have no potential to affect to affect potential no have should fibronectin
are that molecules these whether .1 family peptides family
, releasing hormone Regulation of proteins/peptides other than than other of proteins/peptides ) Regulation - - , 4 . knockout is a substrate is a substrate s to 4 4 has not been determined yet determined been not has - - clinical studies of Sitagliptin and the safety information from information safety the and Sitagliptin of clinical studies degradation
peptides ese et al. et D, Marguet ( 3.(i).B. hormone th In addition to In GHRH (4)3.(i).B. glucagon degraded degraded efficiently are that proteins or peptides multiple are There Although it Although DPP altered fibronectin Chem, Biol specific and site active DPP of site active the to binds Sitagliptin affected Based on the above, Sitagliptin Sitagliptin nt of measureme product vivo DPP of in clearance the manyinvolved are pathways degradation the ( assessment results, and results, assessment specificity Acad Sci USA Sci Acad concentrations non- severe toxicities associated with Sitagliptin with associated toxicities severe Moreover
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page17
, , 4 4 in to - -
4 skin - house house , - GIP DPP DPP murine murine erefore after oral J Physiol for the in by by Th and continuous continuous 4 , an in endocrine L L endocrine - degraded by by degraded ( 1 - Sitagliptin is Am - as
1α
and Sitagliptin However -
, clinical toxicity toxicity clinical 947). DPP . inactive product, product, inactive also that there were no no were that there GLP
observed ed, but intravenous intravenous ed, but for leukocytes and for leukocytes and homing of homing is
suggesting that the the that suggesting an ome peptidases are peptidases ome t
1378)
and are considered to to considered are and S than 2 levels 2 of a peptide
- ), plasma increase not did However ), 5.3.3.3.2 the ) no abnormal been no abnormal have isnot directly involved in . 15). 4 smooth muscle contraction muscle smooth - and Sitagliptin is unlikely to to unlikely is Sitagliptin and to form form to
P gland cleavage there there 1994; 1994; 269: 941-
activity DPP eotaxin, and SDF and eotaxin, , , , can also be said alsobe can 4 , , 5.3.3.1.5 - invivo ( It is secreted from entero from is secreted 4.2.3.2.1-
4 in active GLP inactive intestinal intestinal . 2006; 231: 1373- 231: 2006; It is said that SP that said is It - Also 2 knockout mice or non- or mice knockout neutral endopeptidase neutral in vitro in , - . DPP 5, MDC . Dubé Brubaker PL, PE & 4 ( - , However β
and - GLP
. DPP cleaved by AP by cleaved 2.
active peptides were elevat were peptides active - invivo bioactivity - 4.2.3.1.1
LD78 ( from the pituitary from 4
terminal penultimate proline penultimate terminal first - as well. ,
- 17 GLP Exp Biol Med Biol Exp
1) N
activity is - . .,
is in clinical studies clinical in plays an important role in role important an plays J Pharmacol Exp Ther J Pharmacol n
a
., IGF
( Following intravenous administration of administration intravenous Following et al 1α - . inhibition inhibition of plasma 1
is not regulated by DPP by is not regulated - in vitro 2 degradation degradation - regulation of itsregulation SDF 465) converting enzyme converting
, sensation pain in involved bradykinin 4 - specific aminopeptidases, but are efficiently cleaved by DPP by cleaved efficiently are but aminopeptidases, specific 91%
- - ( These findings suggest that suggest findings These , e.g. RANTES, e.g.
GLP
, and concentrations DPP invivo Faidley TD, Ryan JW, et al JW, Ryan 2. ( ( hours
1 - - chemotactic activity or activity in a signaling assay and altered receptor receptor altered and assay a signaling in or activity activity chemotactic 4 and bradykinin - increase a marked in result not did
action because other peptidases were more important more were peptidases other because action 70 s . function in the gastrointestinal tract in tract in the gastrointestinal angiotensin P and is widely distributed in the body the distributed in is widely and
plasma concentrations of the concentrations plasma 2 IGF is not regulated by DPP by is not regulated - neuropeptide chemokines , DPP like growth factor growth like
2 - . Therefore over , Whitehouse Station, N.J., U.S.A. N.J., Station, , Whitehouse Co., & Inc. Merck - bradykinin - E460 293: 2007;
4 , is a GHRH possess possess chemokines Many -
) these chemokines, chemokines, these findings olved in intestinal growth and motility etc. etc. motility and growth intestinal in olved plasma plasma hemokine
in bradykinin involved
SP DPP ( Of
) Substance ) C P . .2 .3 degraded by degraded as well as by as as well knockout mice knockout in changes in their in changes in is concentrations in in concentrations pigs changes in changes
Degradation of Degradation s and is inv inhibition is unlikely to affect bradykinin to affect unlikely is 4 inhibition 4 4, h 1 regulation of the bioactivity of this peptide of bioactivity the of regulation . - - -
immune regulation immune
- ct the bioactivity of GLP of bioactivity the ct bioactivity of GLP of bioactivity DPP whic preliminary study preliminary no was involved, tobe known is SP inwhich etc. saliva increased or reaction es studi toxicity in Sitagliptin of administration of the degradation Substance Substance studies of of Sitagliptin studies affe (4)3.(i).B. and DPP of GLP administration histopathologic DPP believed to believed be inhibition of Endocrinol Metab, Endocrinol major (4)3.(i).B.
did not affect vivo andinsulin hormone IGF into translate always not does Chemokines are chemotactic cytokines that function as chemotactic factors as chemotactic function that cytokines chemotactic are Chemokines by cleaved Another substrate lymphocytes etc. lymphocytes unlikely to affect GHRH affect to unlikely be protected from cleavage by non by cleavage from protected be vitro result selectivity cells
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page18
the and was
, the , in rat ) 1998; 1998;
in rats ability
ss
tandem tandem in vivo / V
89% possibility d dosing in dogs and the in dogs
The absolute absolute The , the from the born the born from .
) of Sitagliptin 5.0 ng/mL R and the reduces and metabolism in mice, in mice, metabolism
al., Lett, FEBS
excretion in rats were inexcretion rats were
the maximum plasma However 4 - et secretion 1.0 the glomerular filtration filtration glomerular the the ,
labeled Sitagliptin labeled - the area under the plasma plasma the under area the 9 mL/min/kg 9 milk milk ed C DPP and After intravenous intravenous After 14
their migration their 1003). and measurements are expressed as as expressed are measurements and and
1. by distribution ( of distribution volume Proost P, P, Proost
( and
dose 1α - - state assessed liquid chromatography liquid ted by active tubular active -
in female rats at 2 mg/kg an mg/kg at 2 rats infemale not fully understood
. ere in vitro The renal clearance (Cl clearance The renal After oral dosing oral After
are
. 82% and about and about inrats . repeated oral dose toxicity studies toxicity dose oral repeated
subject to subject can not be excluded, but no clinically relevant relevant no clinically but can excluded, not be
2004; 305: 1000- 305: 2004; in
and this value exceed value this and
invivo is
18 to 4 hours post hours 4 to the steady and the in dogs to migrate to
,
to born marrow the effects effects proportional within the dose range tested in dogs while while in dogs tested range dose the within proportional
- mL/min/kg mL/min/kg s
) 4.2.2.2.2 actions , rabbits and in rats transfer hours
4 45 - 4 dose in male rats and and rats male in some some
s that degradation of SDF that degradation % 34 mL/min/kg 34
DPP
was was ha et al., Science, etal., 59 , ) placental assay with a lower limit of quantification of of quantification limit with a lower assay ∞
, 0- ) was about about was The doses are expressed as free base and and base free as expressed are The doses ) . these chemokines is unknown is chemokines on these Based on toxicokinetics
and progenitor cells p
AUC pharmacokinetics of Sitagliptin w Sitagliptin of pharmacokinetics inhibitor and progenitor cell progenitor and was about 2 to about was (
Cl , indicating that Sitagliptin , indicating , , 4.2.2.2.1 4.2.2.1.1 ) to date. date. to been observed have ) ( MS/MS 4
- - cells 1/2 between the doses was more than the ratio of the doses in rats . in doses the of the ratio than more was the doses between was reached at 15 minutes 15 at reached was t in rats 3 andabout L/kg dose 4 action
cells - LC ( - ) ∞ ( DPP
0-
max life - C investigated. stem stem it has been reported been it has ( curve time repeat
- Christopherson KW, KW, Christopherson Plasma concentrations of Sitagliptin were quantita were Sitagliptin of concentrations Plasma dogs, and monkeys and dogs,
9 L/kg . , ere in rats was high at about at high was rats in . Summary submitted the data of
the to sma clearance ( clearance sma
and 76, , 1) Absorption
(
SD considers as follows: as considers 7 harmacokinetic parameters of Sitagliptin following a single intravenous or oral dose of of oral dose or intravenous a single following Sitagliptin of parameters harmacokinetic ± in male dogs at 0.4 and 1.6 mg/kg, respectively mg/kg, and 1.6 0.4 at dogs in male about 5 mL/min/kg about .A. rabbits Sitagliptin, a Sitagliptin,
Summary of pharmacokinetic studies ) Summary ( i).A hematopoietic stem stem hematopoietic ii
) unbound rate monkeys mean mean 3.(ii) concentration concentration concentration ( rats, rats, mass spectrometry mass harmacokinetics of or Sitagliptin oral pharmacokinetics and dose The intravenous single 3.(i w and dogs respectively plasma, and dog The p Table in shown are dogs male ratsand female and inmale Sitagliptin PMDA response, above the in described As
hematopoietic that that about was dose oral an of bioavailability the of AUC ratio marrow alsostudied mean pla mean 432:73- 3.( of elimination half elimination 97% pharmacological effects effects pharmacological ofDPP significance
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page19
, , ), A in ·h ·h ·h, ·h, 10
1.8 0.2 0.3 0.3 0.2 0.1 0.4 0.3 0.6 0.2 0.3 0.4 0.2 0.6 0.8 0.3
the
10, .
and 1/2 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
, 13.6 13.6
t (h) about about and a ( 4.7 4.0 1.7 1.9 1.8 2.1 2.6 2.1 2.3 2.4 2.9 4.0 4.2 3.8 4.5 4.7
plasma plasma
labeled labeled /day / - 7.35 μM
C ,
) 15.0 15.0 μM 220 μM 171 171 μM 14 9.88 9.88 μM
3.4 2.0 1.2 2.0 0.1 0.5
limination ss
Radioactivity Radioactivity ± ± ± ± ± ±
V L/kg of ( : E and
).
and
and and fat tissue 8.8 8.1 7.4 9.0 3.2 3.4 1/2 and about- 4
t
after oral dosing in Week 13 at in Week The tissue ), , systemically hours and the mean mean hours and the , M the ratio was about about was ratio the
( μ 23 rea under the plasma 3
-
1.3 1.5 8.2 1.0 3.6 7.1 p
6 l
± ± : A ± ± ± ± to
C /kg) at 2 mg/kg/day 46 40 48 67 (mL/min 9.3 8.8 1.70 1.70 ectively 37.6 μM AUC ,
about about ( oral dosing. up to 8 hours up to distributed distributed
respectively 20 29
, respectively 0.6, were were
respectively, on Day 1 and 1 on Day respectively, ± ± F - 59 82
NC NC NC NC NC NC (%) 31 olume of distribution of olume ·h, , resp 0.1, 89 97 ·h, 24h 0.4 : V in Week 13 in Week
0- 22- ss
V
week, week, of repeated oral administration ,
ranged from 0.5 from ranged
0-∞ h) 13.4 0.10 0.05 0.32 0.14 0.18 2.04 6.78 0.13 0.36 1.35 0.50 1.56 26.9 34.5 29.2 ·
AUC ± ± ± ± ± ± ± ± ± ± ± ± ± 47.6 47.6 μM ± ± ± max
M
was rapidly t 45.2 45.2 μM 2 (μ AUC and about and about
217 161 156 , and bladder 54. 0.46 2.05 4.28 1.23 1.20 15.2 60.9 1.01 2.20 7.11 1.62 7.18 and about and ) intravenous andintravenous
and the
1 and and 0.1 , respectively, respectively,
or a single oral dose of 5 mg/kg of dose oral or a single , respectively, in Week 12 at 100 mg/kg Week in respectively, ·h,
max
lasma clearance lasma 3.57 3.57 and 1 μM Day on respectively, 19
) ·h, C 6.73 2.05 0.13 0.38 6.57 0.05 4.81 0.08 0.24 6.23 : Maximum: plasma concentration
: P
max h, M ± ± ± ± ± ± ± ± ± ± p ng 14- ng Followi ·
about about l about about max C ( (μ C
. respectively, on Day 1 and 40.2 on Day respectively, μM C the ratio was about about was ratio the radioactivity radioactivity , mg/kg ; , 27.8 10.3 0.21 4.00 17.1 0.21 34.1 0.25 1.32 26.5 11.6 11.6 μM 246 246 μM , ) ·h,
9.41 μM
2
in most tissues up to 4 hours following intravenous dosing intravenous following hours up to 4 tissues in most 2 1 4 1 1 2 1 1 ------2
the mean mean the 12.4 12.4 μM and
, respectively 28, - dose pharmacokinetic parameters of Sitagliptin parameters of dose pharmacokinetic max 1
dosing - (h) - 1 t route
0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 and 0.25 , and eye
9) ) 15 ) in male monkeys and and and
per
217 μM
4 3 4 3 4 4 4 4 6 3 3 6 3 4 4 4 N . Single 8.22 1 and 8.22 on Day μM 1 42.5 μM 10 mg/kg/day, , hour bsolute bioavailability bsolute for distribution following following distribution for and
1.67 μM
F F F 1 - 4.2.2.3.1
: A M M M M M M M M M M M M M um plasma concentration plasma um intravenous Sex 3.76 3.76 μM F
(
) Table Table and about respectively, in Week 12, at 30 mg/kg/day, and mg/kg/day, 30 at 12, Week in respectively, to max
t
, respectively 1,
after were 100 mg/kg/day
25 ·h, for for
s . administration repeated by affected are not Sitagliptin of pharmacokinetics , the - 2 2 2 2 5 observed g/kg) 20 60 10 30 0.5 1.5 0.4 1.6 0.5 180 180 Dose 0.7- respectively m 24h 13 ( he ratio was low in the brain ( in brain the low ratio was he time curve, 30, ange - 0- r : Not calculated , T week, repeated oral administration of Sitagliptin (2, 10, 50 mg/kg/day) in male dogs in male mg/kg/day) 10, 50 (2, Sitagliptin of repeatedweek, administration oral (
in Week 12 at 12 Week in ·h, on Day 1 and on Day .
)
NC 10 a single intravenous dose of 2 of dose intravenous a single SD , 14-
about
oute 46.0 46.0 μM ± i.v. i.v. AUC p.o. p.o. about 2) Distribution R life ( - : Time to : reach Time maxim (
up to 4 hour up to 4 and max
and concentration Mean t half and ranged from 0.5 from ranged
41.3 41.3 μM
1
35 Rat max nimal Dog max species A respectively, in Week 13 at 50 mg/kg/day 50 at 13 Week in respectively, respectively, on Day 1 and and 1 Day on respectively, Sitagliptin ( Sitagliptin and mg/kg/day, and 39.3 mg/kg/day, μM μM respectively, respectively, similar trend was observed also for female dogs and female monkeys and it was considered that that considered was it and monkeys female and dogs female for also observed was trend similar and monkeys dogs 3.(ii).A. Following respectively, respectively,
Following t
C especially in the liver liver the in especially high, ratio was The dosing. oral following hours 8 up to Sitagliptin in male rats (n = 3 rats male in Sitagliptin than higher was radioactivity of ratio 12- was trend similar kidney respectively 0.6-
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page20
) . in or of
5% M5 was day dose
- of the of the day
n vitro labeled labeled
33% I and -
C 1) in rabbits of the dose theof dose 14 29% one percent one percent (
M2 - , transport of intramolecular intramolecular .A. s)
) dose
and -
recovered in bile 1.9% ii 1000 mg/kg/
, Sitagliptin was was Sitagliptin , 4.( Twenty “ 22% . hydroxylation at 24 hours post 24 hours at and and
was investigated using using investigated was , for human data]. human for ee
) s 0.8 ” dose [ urine, and feces were also also were feces and urine, - 250 M regioisomer followed by followed , was low at 32% low to was p μ
g ) (2 -
) 10 ( , the transcellular transport of of transport transcellular , the
M6 , and about andabout gp) in vitro in - , M4 glucuronidation (P
, M dose dependent, unidirectional dependent, unidirectional received oral doses of 125 mg/kg/ of doses oral received μ - -
M1 of radioactivity was recovered recovered was of radioactivity , respectively, 4) , time rabbits, dogs, and monkeys dogs, rabbits, 200 -
, , 4.2.2.5.1 4.2.2.4.2 n =
Following a single intravenous dose of 0.5 mg/kg mg/kg of0.5 dose intravenous asingle Following
of the ring piperazine or a single oral dose of 5 mg/kg of dose oral or a single
( carbamoyl 37.3%
.
at 24 0.3 at post hours dose and about - .
0.02 labeled Sitagliptin labeled - 20 - were mainly detected, but these metabolites were at were metabolites these but detected, mainly were glycoprotein or C
, - , N 14 P % at 2 hours post 2 hours at
in the feces up to 120 hours post 120 hours up to in feces the studies using human biomaterials human using studies
mine 53.5 Sitagliptin crossed the placenta and the mean fetal/maternal mean the and the placenta crossed Sitagliptin metabolite excretion in excretion metabolite rats and for dogs about accounted labeled Sitagliptin in male dogs (n = 3 per group), 62.0% per group), 3 = (n dogs in male labeled Sitagliptin 0.45 received oral doses of Sitagliptin ( Sitagliptin of doses oral received , - ) desaturation
C
14 and it was inferred that blood clearance will approximate plasma plasma approximate will clearance blood that inferred was it and respectively 9) for human data] human for
recovery of radioactivity from all tissues was about about was tissues all from radioactivity of recovery ”
(1) In(1) vitro All metabolites identified in human All inplasma identified human metabolites and the blood/plasma Sitagliptin concentration in ratios rats and dogs concentration andSitagliptin the blood/plasma respectively, the . .A.
, oxidative ) per group were about about were ays 7 to 20, ays bolism of bolism meta he
(ii) - 4.2.2.4.1 ( of the primary a As the metabolites of Sitagliptin of metabolites the As 4. and
.1, , 4.2.2.4 , 4.2.2.3.9 4.2.2.3.2 . , 58.9% ( were about 1 about were ratios n = 4
( ee “ ) When t or
[s
the primary amine, amine, primary the over time time over and
sulfation - in vitro in from mice, rats mice, from microsomes liver and PK1 cells expressing murine expressing cells PK1 40.2% - cannulated male rats (n = 3 per group) per (n=3 rats male cannulated N via rabbits, and dogs ,
Metabolism
metabolized
and Sitagliptin was considered to serve as a substrate for P as a substrate toserve considered was Sitagliptin and M
3) 4) Excretion μ ( ( of the dose. dose. the of pregnant rats pregnant declined piperazine ring opiperazine
10 % ng LLC ng bile duct 0.1- ( , rats mice, . clearance hepatocytes hepatocytes minimally minimally and pregnant rabbits and rabbits to 20 pregnant 6 days gestation from . dose anintravenous after hours 24 at administered of
3.(ii).A.
Sitagliptin from gestation d gestation from Sitagliptin concentration plasma Usi ( of Sitagliptin binding protein plasma The mean When levels Sitagliptin in male rats (n = 3 per route per 3 = (n rats male in Sitagliptin in urine and in urine and 2 mg/kg dose of an intravenous following radioactivity of the administered were respectively, mg/kg, 20 5 and of doses oral following radioactivity administered Sitagliptin is minimally metabolized and and metabolized minimally is Sitagliptin Sitagliptin Sitagliptin (10 μM) was investigated. As a result, to 9 or a single oral dose of 2 mg/kg of mg/kg 2 of dose oral single or a observed at 2 hours post 2 hours at 0.66 about and rats in doses at both biomaterials human using studies formed by formed triazol plasma in low concentrations cyclization present in animals 3.(ii).A. Following a single intravenous dose of 2 mg/kg of dose intravenous a single Following
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page21
is that ces, 4 - ies in brush brush 1990; 1990; in the bound ) from ) from
- plasma plasma / and DPP
/day
capillar adverse drug drug adverse cells, salivary salivary cells,
cells) bile, and fe bile, and
cannulated male male cannulated
diabetes mellitus diabetes membrane the tissue the T , labeled Sitagliptin Sitagliptin labeled
- a , ophthalmologic and and ophthalmologic , respectively, , C but the sequence was was sequence the but
is in the found 14 4 - hours after the last after last dose hours the and
both both
2 In rats 17.3% found,
DPP nm
e
or pancreatic duct splenic red red splenic pulp,
1000 mg/kg 250 and 1000 . lymph node lymph , , ar ( respectively, for eye disorders, disorders, for eye ), respectively,
pigmented animals has not been been not has animals pigmented 266). *** exits as exits
in dog repeated oral dose toxicity toxicity dose oral repeated dog in
bound and -
of 2 mg/kg of and
using dose Hepatology, et GW, al., McCaughan ( splenic 4 expression embrane
- at around at around , m
2 of 1190 subjects 1989; 182: 256- 182: 1989;
( 21
The incidences of adverse events and events of adverse incidences The . intravenous intravenous protein level was highest in the kidney, small intestine, intestine, small in kidney, the highest was level 4 protein
0.2% -
s muscle skeletal heart and all clinical studies in Japanese type 2 type inJapanese studies clinical all
of radioactivity were recovered in urine in recovered were radioactivity of
Sitagliptin concentration in milk at at in milk concentration Sitagliptin
s cell epithelial intestinal small . , melanin affinity of Sitagliptin of affinity the melanin s
the across
thymic lymphocytes thymic ( 4. dose ity was recovered in urine and 9.8% and urine in recovered was ity - -
by PMDA bile duct in bile 2 mg/kg of dose oral single a Following melanin affinity of Sitagliptin Sitagliptin of affinity melanin s
. It has been reported that reported been has It , medulla renal ( DPP the .
, and4.2%
et al., Exp Cell Res, Cell Exp et al., s hepatocyte dose ( no clear relationship between the tissue distribution of Sitagliptin Sitagliptin of distribution tissue the between relationship clear no was there -
s ) and subjects of 1190 7.8% of radioactiv of , 76
received oral doses of Sitagliptin doses oral n =) received 4 per group ( ( , 14 day lactation %
% . 77 , , and lymphocyte thelial cell thelial Sitagliptin was considered to be excreted excreted to be considered was Sitagliptin and doses both at concentration plasma thefold up to 120 hours post hours 120 up to In order to assess the risk associated with melanin affinity, eye and skin adverse events events adverse skin and eye affinity, melanin with associated risk the assess to order In endothelial cell endothelial epi Outline of the review ), , Hong WJ, 544, Hong
icant responded as follows: as responded icant an investigation anof investigation asked the applicant to explain the distribution of Sitagliptin into tissues where tissues into of Sitagliptin distribution the to the explain asked applicant expressed and distributed widely that is enzyme is an of . n = 3) Sitagliptin shows only a single absorption peak absorption a single only shows Sitagliptin
, respectively, , ( 4
about 4- about -
respectively, . performed investigated were studies inclinical reported feces up to 96 hours post hours to 96 feces up The appl not always the same and the same always not of distribution tissue and the to explain applicant the PMDA asked histopathological examinations revealed no toxicological findings toxicological no revealed examinations histopathological , studies reactions in thegroup Sitagliptin 6.4 were patients Since PMDA rats pregnant After 64.6% dogs tended to be high in the tissues where high levels of DPP levels high where in tissues the high totended be gestation day 6 to 6 day gestation 3.(ii).B was milk in maternal present ) tissues other duct cells that DPP demonstrated analysis blot Western DPP follows: as responded The applicant form form and a circulating form border and lung, followed by the liver, spleen, and heart in rats heart spleen, and liver, the followed by and lung, 11: 534- radioactivity ratios at 1 and 4 hours after an after hours 4 and 1 at ratios radioactivity
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page22
, , , ) 9 in -
iii) the the ) ely 248 (
( were 3415
of12 3. in the
DPP “ ) clinical that that of kin and Japanese Japanese has been s ) subjects ee only , and rash, and 7.3%
s and subjects information information [ nt increases nt increases
140 respectiv
8 ( - 456
), rash subjects 356 across foreign phase II phase II foreign . of Japanese
] DPP safety ” 4 of does not appear to to appear not does ) subjects 4.1%
( 145 depende in the 50 mg group
), subjects - ,
taking account of taking ) s explanation s explanation 15 and the incidences of of and the incidences kin and subcutaneous and subcutaneous kin of ’ subjects , (
, Across 5 of 12 weeks + 40 weeks 40 + weeks 12 of due to due 1190 ( a treatment period a treatment . 0.9%
2724 pigmentation in 5 occurred pigmentation 456
and s to collect collect to of
4.2%
of subjects and of ) subjects , respectively, for
in pigmented animals etc. has etc. has animals in pigmented and 4 cases of of cases 4 and Sitagliptin Sitagliptin
) were with
3.4% However 2 21 ), period , ( ( and .
169
] considers as follows: , PMDA considers 449 ( ) ”
and 2724 the applicant of on this matter this on 0.4% of subjects were reported were 1.8% subjects
n only was classified as an adverse drug drug adverse an as classified was only 15 ( ye disorders the incidences of adverse drug reactions reactions drug adverse of incidences the (
e and 112 a treatment a treatment ( ),
106 weeks), the incidences of adverse events of adverse incidences the 106 weeks), 1190 as Adverse events of events Adverse 3415 - high incidence in the Sitagliptin group were were group thein Sitagliptin incidence high
, disorders ye . melanin affinity melanin
3.3% e of , , of with with respectively, and the incidences of adverse drug drug adverse of incidences the and respectively,
4.1%
of 18
for for 7
40 09 22 ( although it necessary is although ( subjects -
,
as a caution statement about skin disorders disorders skin about statement a as caution , A201, A202, and P054 A202, A201, were in the 50 mg , group mg 50 in the
ents between Sitagliptin and placebo in placebo and Sitagliptin between ents
etc. : ) categorized 5435 1.2% 3415 - 0.6% respectively, and respectively, ), subjects mg of Summary of clinical efficacy and safety and efficacy of clinical iii) Summary diabetic retinopathy diabetic there should be no clinically relevant bethere should problems relevant no clinically elanin affinity of Sitagliptin of affinity elanin pigmentation disorder pigmentation 2 4 inhibitors reported to the FDA to 4 reported the FDA inhibitors ( and 4.( The incidences of adverse events at Week 12 at Week events of adverse incidences The ), based on the investigation of adverse events in type 2 diabetes diabetes 2 type in events of adverse investigation the on based
- 456 of “ 200 no sufficient data supporting supporting data no sufficient there is no safety isconcer there safety no ) subjects . ,
, (6 studies of ), subjects draft he 100 mg group mg 100 he ), subjects in the placebo group 0.1% ( and 449 and
Adverse events with a with events Adverse )
28 diabetic retinopathy diabetic of cases 2 of which ), 08, and ONO ( s ), subjects in t of
456 2724 ) subjects 100 mg the above the
, 22
( of of
5435- 6.1% 1190 - subjects the incidences of adverse events were 6.2% were events adverse of incidences the events reported the of subjects
36 19 1190 ( ( of
), subjects ) subjects
and 4.9% , and there no were dose disorders tissue subcutaneous and kin 356 etc. after the market launch market the after etc. and s kin and subcutaneous tissue disorders kin and subcutaneous of
events adverse No 35 ; s 2724 ( 3.(iii).B.(4) Studies for effects on skin in monkeys in skin on effects for Studies 3.(iii).B.(4) . 145 of
1.3% “
4.2% for 1190 ) of for for of
117 observed with other DPP other with observed 13
6 , ( of ( ( 5
[see [see and
( post inflammatory pigmentation change pigmentation inflammatory post which of
As described in As described
2.9% patients treated with Sitagliptin in Japanese clinical studies clinical Japanese in Sitagliptin with treated patients ), subjects ( 14 problems problems
. ( studies comparative blind and ONO P055, clinical pharmacokinetic studies of Sitagliptin of studies pharmacokinetic clinical
- - ) 3.7% 0.2% 9.8% ye disorders ye 3.4% e skin 3415 1.2% placebo or active control active or placebo mellitus reaction , subjects
m and distribution tissue the Concerning eczema ( non In and . disorders tissue subcutaneous affect melanin or melanocyte or melanin affect not been investigated and there are there and investigated not been classified as adverse drug reactions drug as adverse classified for adverse events and adverse drug reactions reactions drug adverse and events adverse , weeks lesions skin double were were . studies clinical foreign and Japanese between similar were disorders tissue of inhibition included in the package insert insert package the in included and Summary of toxicology studies” of toxicology Summary similar incidences of eye and skin adverse ev adverse skin and eye of incidences similar the and nature studies on were were reactions were were reactions ), subjects , group theplacebo respectively and phase III studies (12 studies, treatment periods treatment studies, studies(12 III and phase ( in the incidence 100 mg group 100 mg
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page23
.
, , , . ) 14 ngs was fold
, and 1000 2,
n was ( 23-
for skinfor control 750 mg/day) ( (
0
dogs solutio
hydrochloric hydrochloric , 500,
The effects of of The effects . . As a result, no . in mice (males) inmice .
250, , /necrosis and renal weeks)
/0.1 mM /0.1 including tremor and and tremor including 75
were determined to be to be determined were , 27 ) no toxicological findi no toxicological renal pelvis dilatation in in dilatation pelvis renal maximum 100
conducted provide an about , and 3000 mg/kg 1500 and reddish discharge from from and reddish discharge 14, was determined to be 2000be to determined was
, 100 mg/kg/day , and 100 e 2, also compared to the mouse single single to thecompared mouse ***** oral dose toxicity study and no no and study toxicity dose oral
( control
both both
750, ( hypertrophy ) ) was administered at administered ) was 0 at
was max and rats
) C
in dogs were observed were indogs ***** repeated
and hypothermia aqueous aqueous hydrochloric acid *****
***** ,
centrilobular hepatocellular hepatocellular centrilobular were There (
), weeks clinical observations clinical Sitagliptin
week week 2. multiple of the human exposure human the of multiple and 14 AUC ) in dogs 27 weeks 1000 mg/kg 2- hepatocellular hepatocellular (
( ) 4.2.3.2.2
/5 mM 3000 mg/kg 3000 to be determined was
fold ( Sitagliptin ( Sitagliptin 23 , , and , and Sitagliptin ) ***** ,
( red breathing 500 the approximate lethal dos lethal the approximate
) , 4.2.3.2.9 , 4 and increased kidney weight and weight kidney andincreased ty study labo
in mice in assessed in a ina assessed
and in rats in 250
centrilobular centrilobular ,
, 2 mg/kg/day were treated with with treated were d deterioration in deterioration d
. , at )
) methylcellulose The NOAELs in mice and rats inmice The NOAELs . ) - 4.2.3.1.1
(
group
/ about 1- about provides an w/v ***** skeletal myofiber degeneration myofiber skeletal
( Sitagliptin dissolved in deionized dissolved ). Sitagliptin 14 weeks water in the plasma exposure ( exposure inthe plasma
in dogs was
( .
% week oralweek toxici and and toxicity exposure (AUC) at the proposed clinical dose ( dose clinical proposed the at (AUC) exposure
-
0.5 decreased activity decreased in monkeys of the submitted data submitted the of , dose ) s - dose toxicity Sitagliptin ( - were seen
human human . 50 mg/kg , and 4000 mg/kg , and 2000 . As a result, as an increase in deaths was noted in females treated with treated females in noted was deaths in increase an as a result, As . ) in rats 2, 14, 27 weeks ( of Sitagliptin
, and monkeys Mouse 14 ) Mouse toxicity studies were conducted inmice conducted were studies toxicity in males at 1000 mg/kg/day 1000 at in males the at Week at Week treatment discontinued was
red at .1 ) Repeat ) Single 1000, , males and 15 females 15 and males 2 1 Summary dose A study of study A - differences 15 . ( mouthed breathing mouthed or or insuspended 500,
Summary of toxicology studies toxicology of iii) Summary major 1000 mg/kg dose a 1000 mg/kg to up bioequivalent administered. Death administered. occur death tubular necrosis in mice and rats an rats and inmice necrosis tubular As the major toxicological findings toxicological major the As
( 3.(iii).A. In a single oral dose toxicokinetic study toxicokinetic oral dose a single In approximate lethal dose the and observed nose were toxicity Acute of Sitagliptin of study toxicokinetic oral dose, ( 3.(iii).A. study toxicokinetic dose, a single oral In mg/kg 3.( 3.(iii).A
open- Repeat 180 mg/kg/day toxicity and kidney of multiple 1000 mg/kg/day Likewise, the NOAEL in dogs in dogs the NOAEL Likewise, (2)3.(iii).A. mg/kg/day hypertrophy , which revealed which , monkeys in assessed were and kidney skin the on Sitagliptin 250 mg/kg/day tobe determined was (NOAEL) level effect adverse observed no The Mice acid 250, ) 27, 53 weeks administered by oral gavage by administered
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page24
all all 50 and 180
born liver liver
week week , and and , - - ≥ group) they
53 ALT , and , and 1500 , , 14 , , ) - 10, and - and and
renal tubular renal tubular 27 1 male in the adrenal gland 2, prostate gland were observed observed were there wereno . wellabove the d increase ,
, , , ) , 1000, in these studies, studies, inthese 2- , In addition, at 50 at addition, In and was was .
, 4.2.3.2.7 related toxicological toxicological related ) the - 500 ( ) n clinical observations
control ), and reductions in body in body reductions and ( doses than the studies in in studies the than doses 12
determined to be determined - ) 0
1000 mg/kg/day 1000 er
≥ 25.8 μM ere / females 20 and males . As a result As .
( control w groups groups of the rat 2 ( ere observed ere pituitary weight
20 0 w 4.2.3.2.9 he Sitagliptin he increased cholesterol increased week study week , 4.2.3.2.5 4.2.3.2.4 2- ( bronchial sounds weeks, weeks, The NOAEL was determined to be 250 be to determined was The NOAEL astudy at high Since t Since agliptin
. . the of Sitagliptin Sitagliptin of 27 due to the effects of Sitagliptin of effects the to due
d decrease , max 180 mg/kg/day 180 ) studies week C -
necrosis of lobules of mammary gland and of gland of mammary lobules of necrosis
group; both in 27 24 ( ) 4.2.3.2.6 (
entrilobular hepatocellular degeneration and lymphoid lymphoid and degeneration hepatocellular entrilobular thyroid gland weight and follicular cell hypertrophy hypertrophy cell follicular and weight gland thyroid , and 180 mg/kg/day 60, and and in the centrilobular hepatocellular hypertrophy hepatocellular centrilobular were treated with Sitagliptin with treated were , c , female in the 2000 mg/kg/day group mg/kg/day 2000 the in female and
500 mg/kg/day 500 20, ALT .
ophy occurred in females. in females. At ophy occurred and ,
sacrificed early sacrificed 14- ) , ( studies toxicity oral week . 1500 mg/kg/day . in females were treated with Sit with treated were - females and males s for both ) group
) / the ( ≥ 500 mg/kg/day be < 500 to determined was study in this with with breathing mouthed dead/
it has been discussed that these findings were due to effects other other effects to due were findings these that discussed been has it studies toxicity oral week
weeks. As a result, at the dose of 50 of mg/kg/day dose the at result, a As weeks. control
( ), males and 1 and males At group 27- were noted ) were / 53 0
, and 53 6
and the corresponding and the corresponding
, t 2000 mg/kg/day were not present present not were ll infiltration and males at ≥ and males 27- / females 15 and males
A , and open - , and - 52.4 nM 500 mg/kg/day 500 , 15 ( was conducted ) was The NOAEL The NOAEL week oralweek study toxicity , and 27, and . - , 14- 4 .2 , 14 inmales. - - increased increased and were etc. noted necrosis hepatocellular entrilobular week study week c 14, found found were group hunched position/recumbency or head tilt etc. as deterioration i deterioration as etc. tilt or head position/recumbency hunched 53- males and 4 females 4 and males
weeks, weeks, . As a result As . . r necrosis 2, and 4 Rat 14 ity, tremor ity, ( ) ) Rat 2 Dog 2- ) Dog the 14 , and
( for for .3 .2 .4 . increased and increased , eyelid swelling 4 inhibition - males and 15 females 15 and males occurred in males and uterine atr and uterine in males occurred etc. and and found was myocardial degeneration/necrosis etc. degeneration/necrosis myocardial
) , 2 15 ( related effects and the NOAEL the and effects related ( against rat DPP rat against
week oral toxicity studies studies oral toxicity week 50
dogs eagle , alopecia Sitagliptin, with rats treated In infemales. seen were d increase and increased, phosphatase alkaline ce inflammatory and weight in males occurred etc. gain weight in body and reductions findings invarious organs 27- mg/kg/day and in males degeneration (2)3.(iii).A. (2)3.(iii).A. mg/kg/day 750 at females IC than DPP marrow weight drug- Rats Sitagliptin with treated were , of Sitagliptin orderprofile In the totoxicological determine (2) 3.(iii).A. the above (2)3.(iii).A. d decrease and observed were thymus the and spleen, the nodes, lymph of depletion Rats weight had renal tubula had renal 1500 mg/kg/day mg/kg/day B mg/kg/day 2000 mg/kg/day weight gain weight mg/kg/day reduced activreduced studies degeneration myofiber skeletal and
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page25
) 4 - on
500 500 w/v week week week week (
30, and and the and the 53- 12- . Although Although , and and ,
. 10, . athing with with athing 0.5% , isunknown ,
250 Sitagliptin in the 125, gavage following following ,
control) ormed. As a result, result, a As ormed. ( 50 10 mg/kg/day 0 2), the renal toxicity
10 mg/kg/day 10 the effects of of effects the (AUC)
ncrease in the incidence of of incidence the in ncrease
at the same dose the same
plasma DPP plasma Sitagliptin, of opened mouth bre mouth opened were perf were
at
control control
The mean exposure of Sitagliptin of exposure The mean or chromosomal aberration assay aberration and chromosomal . . 1, and the treatment end of
determine y
related i related assay assay - . ) Sitagliptin suspended in suspended Sitagliptin 23 assay ) 4.2.3.4.1.1 exhibited .
( week study week related deaths, renal hydronephrosis, and and hydronephrosis, related renal deaths,
assessment of of assessment or - control control ( was administered by oral by administered was 14 administration human exposure at the proposed clinical dose dose exposure the clinical at proposed human 0
group group elution 4.2.3.2.15
the ( 500 mg/kg/day 500
in the the in 27-
treatment requested requested 25 given
were treated with Sitagliptin Sitagliptin with treated were related effects on clinical observations, body weight, weight, body observations, clinical on effects related fold ) group dose same the studies were determined to be to be were determined studies alkaline alkaline
males males 28- were were FDA) . group there was no treatment no was there micronucleus micronucleus a rodent hours after the after hours week only
, ) 3, 4.2.3.3.2.1 - ) group 24 / dependent manner and thedependent exposure manner and and , an in vitro was about was to
ed oral dose toxicity study in monkeys, this study was conducted. was this study in study monkeys, toxicity ed oral dose
2 , changes neoplastic , and 53- .
- no drug there were week oral toxicity study toxicity oral week , 4.2.3.3.1.1 At week oral carcinogenicity study carcinogenicity oral week 14- - - ( . As As a result . . , skin and kidney weight and histopatholog and weight and kidney skin 10 mg/kg/day 10 mg/kg/day inthe males 2 aqueous solution aqueous acid hydrochloric As non- As , / females 3 and males and 3 week study was determined to be 2 mg/kg/day be to determined was study week ( month repeat month mg/day)
s
/5 mM this finding occurred in in occurred finding this . As a result As . Sitagliptin
- a dose in increased males and 50 females 50 and males Mouse 106 ) Mouse Monkey 14 ) Monkey
) of .1 .5 50 . that ) Carcinogenicity ) Genotoxicity week study week (
in a 3- max - 4 3
C it has been discussed that this may be attributable to differences in sensitivity among among sensitivity in differences to attributable be may this that discussed been it has US Food and Drug Administration ( Administration Drug and Food US , cells mammalian cultured , , mice
istopathological assessment of the kidney was also performed to performed also was kidney the of assessment istopathological bacterial reverse mutation assay mutation reverse bacterial hesus monkey maximum 100 AUC (4)3.(iii).A. ( 3.(iii).A.
the 27 In methylcellulose ICR Carcinogenicity studies were conducted in mice and rats and in mice conducted were studies Carcinogenicity between Treatment Week Week Treatment between sounds bronchial intermittent the reason the reason ( administration of 100 mg/kg/day 100 of administration centrilobular hepatocellular hypertrophy occurred at occurred hypertrophy hepatocellular centrilobular mg/kg/day . organ in any tumors as this finding was not observed in females in females in observed not was finding as this study individuals The NOAELs in the 2- 97.2% to 98.3% of 97.2% inhibition observed was ( 3.(iii).A. NOAEL in the 27- NOAEL (2)3.(iii).A. A using genotoxic not was Sitagliptin the skin Asthe H R 100 mg/kg/day , food consumption (
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page26
) n dose liver liver - at 500 no Japanese
sein the 4.2.3.2.6 ( genotoxic genotoxic maximum , and 500 , and Sitagliptin Sitagliptin
( repeat (4.2.3.4.1.1) (4.2.3.4.1.1) hypoplastic , hypoplastic
150 non-
decrea 500 500 at males in
was administered administered was
nt rib nt
50, s liver function tests liver function tests the 2), abse the decreased incidence of of incidence decreased ( but but
), fold the proposed clinical clinical thefold proposed , was due to due was and cystic degeneration in in degeneration cystic and solution because Sitagliptin is not is not Sitagliptin because
the
; foreign clinical studies, studies, clinical foreign ; P046 P053 control It has been explained that i that explained been has It a report of the US National US the of report a
, , system ) 1 tumors tumors 10,
- aqueous aqueous week oral toxicity study ( study toxicity oral week P052 such as hepatocellular hypertrophy, hypertrophy, hepatocellular as such to related increase in the incidence of of incidence inthe increase related ibutedto
the carcinogenicity study the carcinogenicity - due to the due to be unlikely is finding this 08 was observed observed was cancer breast of and , - control
al gonad ( - hepatocellular adenoma hepatocellular , P040 4.2.3.4.1.3 0 , ( according to
toxicity of 5435
-
in the 150 mg/kg/day exhibiting group thein 150 mg/kg/day hepatocellular P036
and ) pituitary
given , - 26
ONO s studie clinical foreign and Japanese and hydrochloric acid UC ic ,
A P035 were . rabbits and rats in conducted were studies
human exposure at the proposed clinical dose dose clinical proposed the at exposure human ased on overall evaluation of the results of rat rat of results the of evaluation overall on ased P055
) P032 pituitary adenoma pituitary /5 mM . there was a treatment a was there incidence of incidence , P024 , d hepatocellular injury by Sitagliptin by injury hepatocellular and the incidence of fetal rib malformations rib fetal of , the incidence ) group
hypothalam , P054 / atocellular toxicity in this study. in toxicity patocellular this study. r effect in the liver; the rat 14- rat the liver; the in effect r 500 mg/kg/day e
he in female rats may have contr have rats may infemale he exposure ( he exposure there is a correlation between liver tumor development in rodents and and inrodents development tumor liver between is a correlation there , P023 ≥ t
study , , A203 , etc. s alternation cellular basophilic and eosinophilic and in males and females and females and inmales
, )
, P021 methylcellulose s . As a result As . , ) about 19 times the times 19 about week oral carcinogenicity study week oral carcinogenicity A202 -
mg/day ) (P004 NTP is (
w/v
P020 (
, A201 secondary to chronic secondary Sitagliptin study study
.
dependent occurrence of hepatocellular of occurrence dependent
fetal development
0.5% males and 50 females 50 and males - ) Rat106 - , P019 . hepatotoxicity of no exhibiting group A decrease in the incidence of incidence the in decrease A .2 and it has been discussed that b that discussed and it been has Reproductive and developmental toxicity ) Reproductive this . and degeneration at at degeneration and 50 5 no (
and reproductive and developmental toxicity studies toxicity developmental and reproductive and sensitive to tumor promot to tumor sensitive neoplastic changes neoplastic
, P014 maximum 100 embryo (
rats
mice 500 mg/kg/day at 500 observed were liver the foreign clinical pharmacology studies using doses up to 800 mg/day that is 8- doses 800 mg/day up to studies using clinical pharmacology foreign dose In an ( 3.(iii).A.
It has been discussed that the increase the that discussed been has It non- As toxicity developmental and Reproductive in suspended (4)3.(iii).A. showed doseshowed hepatocellular toxicity; and the incidence of liver tumors did not rise significantly in the 150 the in significantly rise not did tumors liver of incidence the and toxicity; hepatocellular mg/kg/day , necrosis in genotoxic; there was no increase in the incidence of tumors in tumors of incidence inthe increase no was there genotoxic; tumorigenesis SD by oral gavage Toxicology Program Toxicology clinical studies, studies, clinical mg/kg/day breast cancer breast direct effects of Sitagliptin on the the on Sitagliptin of effects direct adenoma ofincidence pituitary mg/kg/day toxicity hepatocellular carcinoma hepatocellular mg/kg/day , P010 100 mg/day). tumors in in tumors revealed
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page27
. ; ) 4 - (n of M
μ mean mean group group . As a
7) Fetal rib rib Fetal 4.2.2.3.9 . , 4.2.3.5.1.1 embryonic embryonic 20**, ( was slightly slightly was day and postnatal and postnatal )
1 day prior to priorto 1 day 250, and 1000 /hypoplastic rib /hypoplastic - % paternal general dependent while dependent while )
- 20**- mg/kg/day 500 2.1 in dams, 1.33 in dams, , 4.2.2.3.8 for for ( The NOAELs were (
125,
within the laboratory laboratory the within ). gestation gestation 24h mg/kg/day and 250 ity fetuses ), , and and ,
through ) , it is estimated that the that estimated is it , C
( , but it has been discussed discussed been has it but , ere
) ugh s 343 w There was a trend towards There was a towards trend increased in the fetuses from from inthe fetuses increased , and 1000 mg/kg/day 250, and group . control of )
( 52.4 nM 52.4 9.1% ( 1 - 18/ ( ) dams in the 500 mg/kg/day dams 0 ).
125, 4
finding - In a study on pre a study In 2 litters were not dose ) and were ), , ) n =n . 6.8% ( 2 ( ese with
4.2.2.3.9 125 control 4.2.3.5.2.3 ( ( ( 250 mg/kg/day , fetuses 0
days prior to mating prior to days 4.2.3.5.2.1
there was a trend towards increased increased towards a trend there was discussed to be related to Sitagliptin to related tobe discussed 62.5, ( ,
), 29 343
. As a result As 20. against rat rat DPP against study with with 27
days prior to mating thromating to prior days to of 1000 mg/kg/day 1000 50 250 mg/kg/day but it has been discussed that this finding is not related related not is finding this that discussed been has it but study
7 5 , maximum 12.71% of resorptions in the control group control the in resorptions of , ≥ ( from IC
s )
control enta into the fetus in rats and rabbits rats and in fetus the into enta ( orally body weight gain was reduced in pups at 1000 mg/kg/day at in pups reduced was gain weight body orally orally treated were 0 the
. Asresult a The incidences of absent rib absent of incidences The 4.6% 6.31% ( incidences the because itagliptin .
ed dependently at 20 to 1500 mg/kg/day of Sitagliptin in the rat rat thein of Sitagliptin 1500 mg/kg/day 20 to at dependently 20 - which has been with with
for maternal general and reproductive toxic reproductive and general for maternal , to increased at increased
) group group that not thgroup exhibit did
6 ) fetal development for maternal general toxicity and paternal and maternal reproductive reproductive maternal and and paternal toxicity for general maternal exceed - were treated treated were orally
) 125 mg/kg/day 125 tobe determined were NOAELs The ) fetal development and of wavy ribs and of wavy male rats dosed dosed rats male mean 20**, mean - . and the incidence and the days days ( from daygestation from )
) to 81% - the incidence was within the laboratory background range ( range background the laboratory within was incidence the group embryo 1000 mg/kg/day 1000 wavy ribs % resorption in females at at females in resorption female rats dosed from 14 from dosed rats female ( litters
, in the pharmacokinetic study rats (4.2.2.3.9) in study in pregnant the pharmacokinetic 20** 46 8.06%
3 1000 mg/kg/day 1000 ( 250 mg/kg/day gestation at embryo Sitagliptin Sitagliptin Sitagliptin n = 22/ Rat study of fertility and early embryonic development to implantation to development embryonic early and fertility of study Rat ( Rabbit
) R ) ) 1000 mg/kg/day
of toxicity studies toxicity .
of .2 .1 .3
from )
/ females 24 and males , fetuses embryonic embryonic
and maximum e in the
. body weight gain was reduced in males at ≥ at inmales reduced was gain weight body on because on dose i 24 , - 343 ( , and variations and
at s of ) wer than the above background data background thethanabove wer 5 resorption in dams at at dams in resorption Sitagliptin , function maternal including development, plac the cross to shown been has Sitagliptin placental transfer, transfer, placental
lo to Sitagliptin because because toSitagliptin (5)3.(iii).A. rats Pregnant
background range background dose almost increased exposure the Rat (5)3.(iii).A. rib milk in rats in milk in maternal excreted to be shown been and has (5)3.(iii).A. determined to determined be for the fetus 3.86% ( 4.2.3.5.1.2 repe Pregnant rabbits were treated treated were rabbits Pregnant mg/kg/day scheduled necropsy scheduled = 19/group) exposur result toxicity toxicity inhibit increased increased different dams at 1000 mg/kg/day dams different than DPP other to effects to be attributable been discussed have and variations malformations that this finding is not related to S to related not is finding this that
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page28
r at of
fo nal
the
150, fetal - , fold 9 are as 50 - fertility ), 22- s similar to to similar s embryo There were no no were There . and control about about (
inhibitors reported reported inhibitors 8, and DPP 4 18 - The exposure (AUC) The (AUC) exposure - and 3 females at females 3 150and was P at 0 . body weight gain and the following 2 studies 2 studies following the to
),
9 male male
- 4, DP - inhibiting inhibiting completely almost
, and 1000 mg/kg/day 250, and
)
9 1 9
- fold the human exposure at the the at exposure human the fold - were observed were , )
100
.
DPP decreased 0.055 > DPP 32-
DPP 125, 4.2.3.2.15 , ( , Compound 1 Compound , which are dipeptidase 9, which are
related findings including related including findings - NOAEL NOAEL the at and -
8, and DPP and 8, 8 - ) - mg/day) M in at doses
DPP against
μ
( 4.2.3.7.7.9 8 DPP
- ( ) were conducted in order to to in order conducted 2) were Compound
control) ( 4 inhibitors ( was about about was 48 (AUC) - neral and reproductive toxicity and the fetus fetus the and toxicity reproductive neral and 4, DPP and 1.2 0.038 ) DPP 0 value
8 and - 50 and reduced body weight gain persisting to the the to persisting gain weight body and reduced
IC
As FDA. the no to reported skinwere 4 inhibitors with with 28 and postnataland development, including maternal -
were treated with with treated were
- exposure exposure
.
4 maximum 100
- The NOAELs were determined to be 125 mg/kg/day tobe determined were NOAELs The , which were determined to be excessive mater excessive tobe determined were which , group for reproductive toxicity and pups toxicity for reproductive
. 30 0.43 3 males at 450 mg/kg/day at 3 males orally 0.018 selective DPP selective DPP The - week oral toxicity study toxicity oral week . ) group 250 mg/kg/day 250 - / ( There were no treatment no were There Compound 1 Compound generation at 1000 generation mg/kg/day the values against DPP- 1 14
mg/day) of 50 250 mg/kg/day 250 inhibition of DPP of inhibition
2 generation . As a result As 20. day tolactation IC
with other DPP
. the F , 2
the
6 2 skin lesions in monkeys observed with other DPP other with observed monkeys in lesions skin F dose same the
were treated treated were
250 mg/kg/day of Drug monkey
) in the 125 mg/kg/day The NOAELsfor maternal ge Table Table Sitagliptin Compound 1 Compound 2 4 ( inhibitors treated the Compound 1 Compound of study toxicity l - . maximum 100 in
group hether ues of Sitagliptin and these compounds uesandcompounds these Sitagliptin of males and 3 females 3 and males . As a result a As . died due to the effects of Sitagliptin and weight loss and reduced food intake were were intake food reduced and loss and weight Sitagliptin of effects the to due died
3 val ( at study for effects on pre on effects for study at
week ora week s R 50 2. n = 22/ activity activity Toxicity studies using non using studies Toxicity ( ) ) 4 12- IC - are associated with Other toxicity studies .1 .4 from from day gestation
selective DPP selective )
) 4.2.3.5.3.1 related effects in the in effects related 125 mg/kg/day 125 6 ( - determined to be determined
.( The all 4. and weaning stage in males inmales stage weaning 450 mg/kg/day 450 - - Monkey
gestation day 16) proposed clinical dose ( dose clinical proposed 3.(iii).A maternal general toxicity and toxicity general maternal toxicity for reproductive at the NOAEL reduced food intake in dams at ≥ in dams intake food reduced post and toxicity. Thus, the 500 mg/kg/day group was terminated on gestation days 15 days on gestation terminated was group 500 mg/kg/day Thus, the toxicity. . performed not was evaluation toxicity treatment to FDA the using non- using w investigate further (6)3.(iii).A. (a) Rhesus monkey
Sitagliptin (5)3.(iii).A. ( noted also in animals other 62.5 were DPP Skin lesions in monkeys monkeys in lesions Skin Sitaglipt the of administration following found lesions were DPP plasma
function human exposure at the proposed clinical dose ( dose clinical proposed the at exposure human Pregnant rats rats Pregnant shown inshown Table
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page29
, 3, in of 50 50 50 30
and
and 450 and
), + +
+ of the Plasma Plasma 2 + 50 2 + 0 10→ females 10
2 related to to related at ≥ group ,
control
and ( male in the 1 male indicative
the following following the , 0 swelling swelling 50 ,
and prostration / 30 mg/kg/day →30 mg/kg/day ,
+ .
considered redness . As a result a As . compared to to 64.2% compared out
in males in the the in males in glomerulopathy etc. were were etc. glomerulopathy week oral toxicity study study toxicity oral week 50 mg/kg/day . As a result . As -
and edema/inflammation ofedema/inflammation the + skin lesions reported, the lesions skin to
14 , , and multifocal inflammation with with inflammation multifocal )
, 4 inhibition , - in a clinical setting clinical a in lateral recumbency lateral
50 mg/kg/day monkey monkey ,
, which were swelling in the hind limb area etc. area limb hind the in swelling
4) mg/kg/day
was observed at 2 hours dosing at after 2 observed was 4 inhibitors +
- dilatation
the etc. glomerulopathy 4.2.3.7.7.10 ar
150 mg/kg/day 98%
. group ≥ One animal sacrificed early in the 0 the in early sacrificed animal One
As lesions As renal in the Compound 2 groups were noted. were noted. 2 groups thein Compound , and 50 , and . .
were treated with Compound 2 at 2 Compound with treated were 50
in males in the 10 the in males in observed were 29 + renal tubul in combination with metformin with combination in selective DPP selective the cerebral cortex and hippocampusin the and hippocampusin cortex cerebral the , were treated with Sitagliptin + metformin+ Sitagliptin with treated were were found dead/sacrificed early. One male at male One early. dead/sacrificed found were , lesions skin As
. 10 ies 9 inhibition, but not DPP ncreased in Week Week in ncreased i ) - ) group , in ( / 50, had focally extensive areas of hemorrhage in their brains in their hemorrhage of areas extensive had focally degeneration and degeneration
+ ) group →30 mg/kg/day were observed 2
≥ ≥ about of activity 4 mg/kg/day group and 1 femaleeach in the 0 10 - ),
8 and DPP - 4.2.3.7.7.13 excessive scratching at 450 mg/kg/day scratching excessive toxicity stud toxicity ( , dose
, and 10→30 , and
tissue subcutaneous 9) DPP dose 50 mg/kg/day renal tubular renal -
saponification of fat tissue at fat tissue of saponification , and 50 + 50 and males and 3 females 3 and males neuronal necrosis etc. necrosis neuronal and female at 50 mg/kg/dayfemale
discussed that based on the results of results the on based that discussed metformin group was sacrificed early sacrificed was group 3
50
( taxia, tremors, and increased plasma lactate in the 50 in lactate plasma increased and tremors, taxia, female at at female +
/ females 3 and males and week oral toxicity study of Compound 2 ( Compound of study toxicity oral week s + A 1 - has As skin lesions skin As 3 Dog repeat Dog
) 23 and 1 and of (a) and (b) studies using non- using studies (b) and (a) and of group were found dead/sacrificed early dead/sacrificed found were group , lactate plasma increased and bicarbonate serum decreased exhibited group .2 and , increased in Week Week in increased ( As renal lesions renal As at 2 hours after dosing in the dosing after hours at 2 activity was comparable to control except that it was inhibited by ab by inhibited was it that except control to comparable was activity Significant inhibition of DPP of inhibition Significant /day week oral toxicity study toxicity oral week - 4 etc. in the Compound 1 groups Compound the in etc. - vacuolation vacuolation Monkey Compound 1 groups compared to the control group. group. to control the compared 1 groups Compound 14 hesus monkey hesus Sitagliptin dose dose Sitagliptin ) 4.2.3.2.15 Compound 1. Compound tissue subcutaneous skin . group extensive degeneration and necrosis of nervous tissue nervous of necrosis and degeneration extensive mg/kg/day 10→30 ( (a) ( dogs Beagle (b) (b) the of edema/inflammation mg/kg/day
mg/kg/day 1→12.5 inflammation multifocal and mild group mg/kg/day DPP control The applicant ( the aggregation of mononuclear inflammatory cells inflammatory mononuclear of aggregation noted. . acidosis lactic mg/kg/day R each in the 10 mg/kg the FDA are associated with deterioration in clinical observations including unformed stools unformed including deterioration in clinical observations and (6)3.(iii).A. studies were conducted to evaluate the potential toxicity and toxicokinetic interactions of Sitagliptin in in Sitagliptin of and interactions toxicokinetic toxicity potential the evaluate to conducted studies were . metformin with combination Since Sitagliptin may be used in combination with metforminwith combination in be used may Sitagliptin Since
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page30
. n in as be 20
the , and
cells
+ There group
.
50 times the the times ltration asked the the asked
infi The exposure exposure The
. ) between ) between in the 14- Furthermore ( dogs , female
which should , and20, max , liver findings were were findings liver , + 50 mg/kg/day y for metformin for
+
10 and C
, 1 animal sacrificed early early sacrificed animal 1 , metformin
. degeneration 20,
24h mbination of Sitagliptin and of and Sitagliptin mbination ar 0-
+ 20 mg/kg/day. group dose . - 2 50 + toxicity studies, PMDA studies, toxicity 20,
. regeneration myofiber +
mg/day)
considered that skeletal myofiber myofiber skeletal that considered it is in the 0 dose - , , which should be suggestive of reversibility at and abnormal respiration characterized by by characterized respiration abnormal and
ive of in the dog repeated oral dose toxicity studies studies toxicity dose oral repeated dog the in
s oxicity of Sitagliptin of oxicity 1500 mg/kg/day 1500 and at changes such as death was about 180 about was as death such changes
30 All of the above findings can be monitored easily in in easily monitored can be findings above the of All
the NOAEL forthe the NOAEL co suggest . for Sitagliptin and 20 mg/kg/day and for Sitagliptin
.
maximum 100 week study week metformin be
muscle satellite satellite muscle by surrounded myofibers degenerated
alone irreversible 10 mg/kg/day ng animals had mild renal tubul mild had animals ng
hepatocellular hypertrophy and inflammatory cell and inflammatory hypertrophy hepatocellular ≥ min
1500 mg/kg/day 1500
The ataxia and tremors observed in thein 50 observed tremors and The ataxia in toxicokinetic parameters (AUC parameters toxicokinetic in in the 53- the in the ≥ . ) 4.2.3.7.7.14
were not serious injuries serious were not ns including tremor
end of observation period each day period observation dose end of and the ( by PMDA - which should should which ved , resulting in resulting related. Skeletal myofiber degeneration noted at 50 mg/kg/day at noted degeneration myofiber Skeletal -
andsurvivi 5 . transient ataxia and tremors occurred tremors and ataxia transient differences , hours post how to assure the reversibility of t the reversibility toassure how 7 necrosis necrosis 500 mg/kg/day 500
at 500 mg/kg/day and 500 mg/kg/day reversibility
were treated with Sitagliptin + Sitagliptin with treated were ≥ Reversibility of toxicity of Sitagliptin of toxicity of ) Reversibility . As a result As .
1 noted Outline of the review o recovery study has been performed in repeat in performed been has study recovery o findings were observed at at observed were findings .( . week oral toxicity study perimysium were seen were perimysium -
mouthed breathing observed at observed breathing mouthed ) group renal tubular renal week studies was slight in severity and inseverity slight was studies week 5/ idney mg/kg/day 10 mg/kg/day to be determined was metformin were no significant were determined to bedrug to were determined
observatio inclinical Changes In order to evaluate the toxicity of Sitagliptin in combination with low with in combination of Sitagliptin toxicity order the to evaluate In or metfor Sitagliptin and combination 3.(iii).B , studies 2 above of the results the on Based 16 (b) Since n obser were groups mg/kg/day = observed not was this finding had observed at at observed open- 3.(iii).B follows: as responded The applicant stud toxicity dose oral repeated rat the in findings toxicological major the Among Although the applicant explained that if the findings noted in dogs occur in humans, these findings can can findings these humans, in occur dogs in noted findings the if that explained applicant the Although humans degeneration does degeneration not progress and is reversible the liver liver the K resolved between between resolved indicative of indicative applicant toapplicant explain (AUC) at mg/kg/day 1500 in the 27- human exposure at the proposed clinical dose ( dose clinical proposed the at exposure human
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page31
. , ), were since dated
Partial groups species tremors
n “ 4.2.3.2.6 (
there were no no were there t elevations of of televations While maximum100 mg/day), disorders
( adverse events events adverse ,
toxicity study is study toxicity ).
gp transport after transport after gp - decreased activity activity decreased dose - 180 mg/kg/day observed in rats treated treated inrats observed
and is considered to be be tois considered and and
≤
, , disorders system nervous a caution statement in the the in statement a caution s related findings in clinical clinical in findings related blind comparative studies comparative blind the Sitagliptin and placebo the and placebo Sitagliptin evaluated based o based evaluated
- , which provides an exposure an exposure , which provides maximum 100 , respectively , ing ( central nervous system; skeletal skeletal system; nervous central CNS been been
2.6.4.4.5) ( clud
. week oral toxicity study oral toxicity week not the incidences of the incidences in 38 μM
l dose hepatotoxicity 14- in repeat the dog
PMSB/ELD Notification No. 655 No. Notification PMSB/ELD and ( 09),
- 8 times the human exposure at the proposed proposed the at exposure human the times , 500 mg/kg/day in the 500 mg/kg/day - double inJapanese
max 23 5435 - ≥ , C were similar between between similar were Therefore, as the as Therefore,
mg/kg/day .
transport system transport tumors in the carcinogenicity study in thetumors carcinogenicity
31
the necessity of necessity the ONO gp . - abnormal respiration, tremor respiration, abnormal indicated that indicated the is about adverse events categorized as categorized events adverse P ular
L of 2 to dogs ( to dogs 08, , respiratory and musculoskeletal disorders, , respiratory AE Furthermore eneration observed in dogs are unlikely to occur in humans in to occur unlikely are dogs in observed eneration . related effects may have occurred due to transien to due occurred have may effects related 5435- - the findings noted in rats are unlikely to occur in humans in to occur unlikely are noted rats in the. Thus, findings dose toxicity studies” dose toxicity has been has - - , about 100 μM) in the rat
including it the symptoms did not worsen with prolonged did not prolonged worsen with ofsymptoms the any reversible; be max CNS ONO by the end of observation period studies each pharmacology day ; safety repeat 50 mg/kg/day
, mg/day) the
disorders musculoskeletal the findings observed in dogs are unlikely to occur in humans. in humans. to occur unlikely are in dogs observed findings the and but showed no effects on respiratory function or function respiratory on effects no showed , related to hepatocell P055
) specific to dogs specific 10 is
including other findings noted at noted other findings including toxicity study, the reversibility of toxicity has of toxicity the reversibility study, toxicity
ation tended ation tended to asked asked the toapplicant explain ity studies in other animal species and it is considered that dogs are sensitive sensitive are dogs that considered is it and species animal other in studies ity Sitagliptin is a substrate for for substrate a is Sitagliptin
, P054 nervous system disorders system nervous . dose 4.2.1.3.4 although . However, - maximum 100 ( as toxic ≥ 1500 mg/kg/day (C
and PMDA , A202 . repeat between the Sitagliptin and placebo groups and placebo the Sitagliptin between considers as follows: as considers
dose nitored easily, the NOAEL for abnormal respiration is 2 is mg/kg/day respiration abnormal for NOAEL the nitored easily, - related findings in clinical observations or skeletal myofiber degeneration were not observed in in were notobserved degeneration myofiber or skeletal related observations in clinical findings al dose 500 mg/kg/day 500 related effects effects related - hanges in clinical observations observations inclinical hanges 4.2.1.3.3 , A201 revision of the guideline for the of guideline revision ) April 5, 1999 with with ose toxicity studies are considered to be related to the central central tothe related tobe considered are studies toxicity dose oral repeated in dog the observed system nervous abnormal respiration resolved resolved respiration abnormal ( and the exposure (AUC) at 180 mg/kg/day at (AUC) exposure and the clinic at the NO (AUC) theAlthough exposure CNS repeat similar deg myofiber skeletal and observations insert the package in statement a caution include to no need is there PMDA studies clinical ingroups In each In categorized
follows: as responded The applicant C be mo (AUC) that is almost comparable to the human exposure at the proposed clinical dose clinical proposed the at exposure human the to comparable almost is that (AUC) mg/day) point this of account also taking insert, package drug- clinica proposed at exposure the human the to comparable almost degener myofiber duration theof of incidences treatment; and respiratory disorders, and or these findings are or these findings ( occurred at occurred excreted from the brain, from excreted P via excretion of saturation from resulting brain, the in concentrations Sitagliptin theof administration
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page32
,
). yme liver liver P023,
, A203 , foreign foreign and the erefore
) may have placebo or 09; ( P021 . Sitagliptin Sitagliptin . . Th , - ) .6 4.2.3.2 , A202 thyroid gland
P053 affecting ( 5435 - , P020 , , A201 , P052 , 4.2.2.4.6 cellular alternations is is alternations cellular toxicity study and an and an study toxicity ONO
P019 12] , fold) between the highest thefold)between highest occurred early occurred also in the carcinogenicity , from the standpoint of the of standpoint , from 08, , P040 Based on the analysis of of on the Based analysis - , dose - events adverse P014 5435
, P036 - , CYP3A4 ( , CYP3A4 . repeat week oral toxicity study were the the were study toxicity oral week s (about 19- Therefore week oral toxicity study oral toxicity week rat ONO . , P035
centrilobular hepatocellular hypertrophy hepatocellular centrilobular a laboratory based on plasma concentration plasma on based
t the increased incidence of hepatocellular of hepatocellular incidence increased t the ic enzyme study but
, P055 , , P024 , ,
inrat 14- the
. and carcinoma and hepatocellular hypertrophy due to hepatic enz hepatic to due hypertrophy hepatocellular metabol P054 32 data up to Treatment Week Week data up toTreatment P023 was not secondary to hepatocellular injury associated associated injury to hepatocellular secondary not was , [ secondary to to or secondary by be induced to wereetc. considered
s about the safety in humans safety the about , e.g. he incidence ofhe incidence A202 t week study were similar between the Sitagliptin and control control and Sitagliptin the between similar were study week , P021
d liver weight in weight liver d carcinogenicity , 500 mg/kg/day 500
induction and hepatocellular injury injury and increased and induction hepatocellular control and Sitagliptin the between similar were etc.
he primary he primary eosinophilic and basophilic cellular alternations and cystic and cystic alternations cellular basophilic eosinophilic and
t )
, A201 , P020
500 mg/kg/day , , P010 studies, clinical ; foreign P046
it has been reported that there is a significant correlation between between correlation significant is athat there reported it been has , P053 cell hypertrophy cell 10, - , P019 increased incidence of eosinophilic and basophilic and basophilic eosinophilic of incidence increased There is an adequate safety margin margin safety adequate is an There , to NTP
potential concern concern potential , P052 08 by ,
- Japanese clinical studie clinical Japanese P014 (
epithelial epithelial the combined findings combined the does induce does not it is inferred that these changes had occurred in the early phase of the of the phase inthe early occurred had these changes that is inferred it groups. ,
P040 5435 ) , ation observed in theation observed 14- studies accepted the response. the response. accepted ONO- , P036 follicular findings observed at ≥ at observed findings Liver carcinogenicity in rats carcinogenicity ) Liver Japanese clinical studies, studies, clinical Japanese 2 ( However asked the applicant to explain the possibility tha possibility the explain to applicant the asked .(
. , P055 , P035 liver n the rat carcinogenicity study n the rat carcinogenicity n Japanese and foreign clinical studies clinical foreign and n Japanese groups and the study carcinogenicity function and cellular infiltr cellular and Sitagliptin of study weight and weight inductionhepatic. enzyme induction. enzyme of hepatic suggestive change be a to considered carcinogenicity I degeneration in the liver were noted at were inthe liver noted degeneration , P010 studies, clinical tumors observed in the rat carcinogenicity study in study the tumors observed rat carcinogenicity rat 14- the and this study in the doses and xicity to hepatocellular The baseline from change follows: as responded The applicant 3.(iii).B PMDA and a with Sitagliptin Then, PMDA hepatic enzyme hepatic of suggestive changes a in tumors liver of incidence increased that hadinjury to hepatocellular due infiltration cellular and induction hepatocellular hypertrophy and increase hypertrophy hepatocellular I , P054 s adenoma hepatocellular of incidence the increased , P024 at the clinical dose clinical the at dose producing no liver tumors in rats and the clinical dose clinical the in rats and tumors no liver dose producing tive comparator active humans in carcinogenic be to is unlikely Sitagliptin
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page33
in In not , . The was was
250, s om a .
hepatic hepatic . Thus, . Thus, was
125, metastatic metastatic in the 500 in the 500
etc. in rats were Therefore no
butes little to to little butes in rats did not didin not rats
there were no and moreover, and moreover, 62.5,
. , evaluated body weight loss loss body weight
0, , 250 mg/kg/day
≥ was not was As a result As Sitagliptin Sitagliptin in any of the developmental of developmental the in any
fetal toxicity fetal
- ), 20. should be suggestive of suggestive be should to stimulatinghormone
and metabolism contri and metabolism findings study. study. fetal development
fetal weight at - . Sitagliptin by induction enzyme hepatic group mg/kg/day) dose (500 high the - thyroid ,
live related related or - hepatocellular tumors observed tumors hepatocellular embryo
developmental toxicity toxicity developmental ) (4.2.3.5.2.4 group
the
suggesting 33 food intake decreased decreased intake food group, 500 mg/kg/day the in in thyroid
) 4.2.3.5.2.3 man exposure at the proposed clinical dose exposure dose the at clinical proposed human fold the at the highest or producing no hepatotoxicity liver dose
there are no direct or indirect data on hepatic enzyme enzyme hepatic on data indirect or direct no are there data data ) from gestation days 7 days gestation from n = 10/ , dings observed in rats in observed dings
( fin AUC re no treatment re no (
specific sex ratio or skeletal and visceral malformations/variation visceral and skeletal or ratio sex
pment study ( study pment was aboutwas 19- 125 mg/kg/day
there we there , toxicity studies toxicity
and Although there are no direct data showing hepatic enzyme induction by induction by enzyme hepatic showing data no direct are there Although
gland thyroid . as not evaluated and as evaluated not liver tumors observed in rats are unlikely to occur in humans to occur are unlikely rats in observed tumors , liver dose w - even if hepatic enzyme induction occurs, there will be no marked decrease in in decrease marked no be will there occurs, induction enzyme hepatic if even atocellular injury by Sitagliptin are not necessarily necessarily not are Sitagliptin by injury induction hepatocellular and enzyme
fetaldevelo ,
observed tumors hepatocellular not is genotoxic; Sitagliptin since - ; and the exposure were administered orally administered were ,
animals other 4 maternal In GT study in study pregnant rabbits - . repeat liver and liver hepatic UDP ince Sitagliptin is primarily excreted unchanged excreted is primarily Sitagliptin ince the reproductive and developmental toxicity and developmental study reproductive rabbit in evaluation Toxicologic . data as reference study S However identified ) , related effects except for slight reductions in reductions slight for except effects related ranging or - 3 . -
asked the applicant to discuss developmental toxicity in rabbits, using the results fr results the using rabbits, in toxicity developmental todiscuss applicant the asked .( considers as follows: as considers asked the applicant to explain to explain applicant the asked
rabbit embryo
dose 500 mg/kg/day 500 CYP the a maximum 100 mg/day) measured in rat inrat measured . induction elimination clearance elimination concentration the plasma . Sitagliptin induction by enzyme PMDA The data supporting the applicant’s view that the that view applicant’s the supporting The data tumors in mg/kg/day) rats tumors (150 ( Sitagliptin secondary to secondary g the dosing period. As to embryoto As period. dosing the g durin resolved which transiently, treatment thefor examined not were fetuses In mg/kg/day group addition to the above results 3.(iii).B follows: as responded The applicant As PMDA sufficient focus was was focus maternal animal in 1 maternal were observed abortion a spontaneous and intake and food reduced 62.5 at parameters toxicity istopathological changes were similar between the Sitagliptin and control groups and groups control and Sitagliptin the between were similar changes histopathological affect the survival rate as the direct cause of death in the carcinogenicity study inthe carcinogenicity of death cause the direct rate as the survival affect terminated due to excessive maternal toxicity and and toxicity maternal excessive to due terminated follows: as responded The applicant In PMDA preliminary and
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page34
9 4 - - are and that ) and 9 8 - - DPP DPP lesions , which , which ranging
- based on DPP DPP and skin 98% at their dose 8 4.2.2.3.2
- and ≥
the for Compound 2, for Compound . However, as no no as . However, 8
- DPP , but did not induce in the
(A201, A202, P054, P054, A202, (A201,
. DPP
in foreign clinical studies studies clinical foreign in in monkeys monkeys in lesions skin the difference in difference the
low cellular permeability of of permeability cellular low inhibition of rash mg/kg/day fetal development study fetaldevelopment 4 - - ical studies studies ical attributed to the the to be attributed , which may activity could not be determined determined not could be activity skin lesions in humans due to a a to due in humans lesions skin
4 inhibition and 4 inhibition 250 mg/kg/day and
- associated with of due to due to DPP
( skin the in distributed
at 125 at at ≥
caused by effects other than than other effects by caused
embryo in vivo in were similar between the Sitagliptin and and Sitagliptin the between similar were
eczema the ) 2000 27, December dated , is available not ibition of inh ibition percent showed showed
in Japanese clin Japanese in
development 1834
developmental toxicity can be evaluated evaluated be can toxicity developmental
, although 34 in vitro activity activity and
Detection of Toxicity to Reproduction for for uideline to Reproduction forToxicity of Detection , 4 - the . group in Sitagliptin the observed e not more serious skin lesions were predicted were lesions skin serious more possible possible the incidence of theincidence As . has been confirmed to be confirmed been has . the response accepted and
were insufficiently inhibited
caused reduced body weight reduced caused 09) 9 - - 5435 Sitagliptin skin lesions wer lesions skin DPP - reported to the FDA are to FDA the reported 4 inhibitors endoenzymes - skin lesions reported lesions skin to were the FDA , but Sitagliptin Sitagliptin 4 inhibition. and s - are fetal development study fetal development PMSB/ELD Notification No. No. Notification PMSB/ELD - ( 8 the
- here should be no relationship between between DPP be no relationship should here using Sitagliptin and Compound 1 Compound and Sitagliptin using 9 for effects on skin in monkeys effectson skin in for -
inferred is it 2, Compound 1 and Compound of exposures plasma values and T 08, ONO 08,
- . inhibition of monkey DPP of monkey inhibition 9 were both inhibited sufficiently 9 were both inhibited ies ies 50 - that DPP kin and subcutaneous tissue disorders subcutaneous and kin the applicant to explain the basis for discussing that the discussing for basis the tothe explain applicant DPP
s embryo
or
5435
- that and ) Stud the .
not DPP not , but 4 fetal toxicity was evaluated using 2 dose levels in levels dose 2 using evaluated was toxicity fetal in accordance with “Revision of the G the of “Revision with inaccordance percent percent fetal death or external abnormalities and the NOAEL for the fetus was determined to be 125determined for fetus was the NOAEL the and fetal abnormalities or death external 8 asked - asked the applicant to explain the skin lesions produced by Compound 2 were mild in severity mild 2 were Compound by produced lesions skin .( inhibition - -
9 8 and DPP - - the toxicity stud the DPP ed on the IC ased on s embryo DPP reported to the FDA because the to FDA reported the The applicant responded as follows: as responded The applicant observed with other DPP other with observed As mg/kg/day Embryo follows: as responded The applicant PMDA B , embryos/fetuses rabbit PMDA highest dose highest respective DPP a inhibition selectivity between monkeys and humans is unknown. However, the incidence of adverse events events adverse of incidence the However, is unknown. and humans monkeys between selectivity as categorized ” Products Medicinal P055, ONO P055, (P010, P014, P019, P020, P021, P023, P024, P035, P036) P035, P024, P023, P021, P020, P019, (P010, P014, was notwas difference in the selectivity for enzyme inhibition between humans and monkeys humans inhibition between for enzyme thein selectivity difference toxicologically significant developmental toxicity was observed observed was toxicity developmental significant toxicologically study and and study 3.(iii).B than Compound 1, Compound 2 than Compound higher with but possibility 2 Compound , PMDA studies two these of results the
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page35
to in 38 the the the
, ative ative . There of ≥ )
because, because,
develop obstacle max
fold compar herefore C in humans at at in humans an
45- associated with associated ies, t the skin lesions lesions skin t the and if skin disorders activities but no skin lesions but lesions no skin ·h are come , 9
- , about max ion are associated with with associated are ion C
max C , are unlikely to unlikely are , 105 μM toxicity stud toxicity inhibit 9 and the plasma exposures ofand the plasma 8 and DPP - of ≥ fold;
the -
40.9 μM ontinued has been included in the the in been included has ontinued in
DPP inhibitors and AUC the plasma concentration the plasma
4 9 are not available and each enzyme in enzyme and each 9 are not available week oral toxicity study of Sitagliptin of study toxicity oral week - - - and reported to the FDA
14 8 week oral toxicity study of Sitagliptin, , about 28- - AUC DPP
14- . A caution statement that that statement caution A . DPP AUC
relative to relative (
8 and DPP to support the applicant’s view tha view applicant’s the support to ) - .
35 inhibitors monkey 236 μM that
selective selective 4 - - of monkey
skin lesions in monkeys lesions skin non the dependent manner at manner dependent the - sufficient the In inhibition of DPP theof percent inhibition
100 mg/day . in clinical studies
Compound 1 and Compound 2) 1 and Compound Compound , the development of skin lesions is unlikely to be is lesions unlikely skin of development , the inhibition of DPP inhibition (
s but the possibility the but , .
develop, administration should be disc should administration develop, maximum (
erefore , as seen with seen as , sufficiently inhibited at the low and mid doses of Compound 2. T of Compound doses and mid low the at inhibited sufficiently percent percent
4 inhibitor inhibition - sults from the from sults the re on Based here is an adequate safety margin margin safety adequate an is here 9 - . skin lesions skin and t
DPP can not be made based on based made be not can skin tissue disorders between the the between disorders tissue as skin categorized events adverse of incidence in the fferences
in monkeys treated other DPP with in monkeys and considers as follows: as considers espect to the relationship between between totherelationship espect found 8 the data on in on vivothe data - selective DPP selective ned so farobtai are data not clinical skin lesions can not be ruled out ruled be not can lesions skin , ), 4.2.3.2.15 ) reactions hypersensitivity ( Sitagliptin of administration the following humans ( Th (draft). insert package were no di groups placebo and Sitagliptin were were the proposed clinical dose clinical the proposed non- With r With PMDA groups placebo the clinical use of Sitagliptin of use clinical the μM although skin lesions worsened in lesionsa dose worsened skin although discussion have been have not may cells non- observed observed DPP the exposures plasma the in resulted highest dose
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page36
)
was
style style arget arget max ), t ( , max C min and of the was to be to was be confidence (
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The main study results are described described are results study main The fed ( ( . dialysate for formulation
).
0.52 ( max **********) (geometric standard deviation) deviation) standard (geometric were submitted: 1 Japanese clinical study clinical Japanese 1 submitted: were
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4.08 were used were
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was was
36 1.62 fasted Capsule formulation Film Proposed commercial formulation ***** ******* ∞
study in Japanese healthy in study Japanese healthy 0-
types of the drug substance AUC
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1.15,
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to assess the pharmacokinetics of the the of pharmacokinetics the assess to used in Japanese clinical in studies used clinical Japanese
the geometric mean mean the geometric ***** ***** , P006 effect
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Drug substance was quantitated by by quantitated was
and biopharmaceutic studies biopharmaceutic food in the fasted state and and state fasted the ) in formulation commercial proposed the of as Sitagliptin
g/mL
are presented in Table 3. Table in presented ) are
period, to
mg A112 2- 08 hours ) and Formulations , 1.02] , - )
. showed that showed , 0.1 μ was conducted conducted was 3 , 6 203
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[ Study Number Study
Table Table 10 P013 - A201 P054 ONO- P046 mg valuation data valuation day washout period was included between the two periods the between included was washout period day * * 20 analysis analysis [ E
The geometric mean ratios of ratios mean geometric The
and the geometric mean of AUC mean geometric the and 1.5 hours ( for plasma for
capsule . ( once daily in the mor the in daily once
( . analyses safety and the in pharmacokinetic included were subjects treated a 50-
( proposed commercial formulation commercial proposed the of study effect food and Pharmacokinetic nM P076 ) and a 7- and Summary of the submitted data submitted the of Summary 1 studies
s were 0.98 were s Phase I Phase I and 4 foreign clinical studies and 4 foreign clinical
Phase II ( Phase III
Development ) 92.9 mg tablet mg phase of study of phase ( .A. .A ********************, Summary of biopharmaceutic of studies) Summary and associated analytical i
harmacokinetic ) P076 , 5.3.3.4.2 P 12 the of All breakfast ( interval was 2.5 hours was administered administered below. below. The from results the following a 50- number of cases of 12 of of cases number formulation of 50 single oral dose A 366 A randomized, open- randomized, A 4.(i) ( Sitagliptin in Sitagliptin human In the clinical development of Sitagliptin, 2 Sitagliptin, of development clinical the In data 4. Clinical 4.( 4.(i) was 0.5 ng/mL was clinical drug product drug
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page37
. , 4 on the 1.10
[
) of each subjects increased
ntinuation hereinafter confidence confidence 1.21 subjects [ (
ation of ation of
4
there were no ; ere ) formulation . ,
nce data nce 90% events] after the were regarded as ) 6 its potassium of which 5 events of of 5 events of which
tablet ), including laboratory test test laboratory including , Refere female and male ( ] with erum leading to disco to leading
s ) subjects [ after the administr after 4 ( asted administration, ventricular administration, asted * 20** f ( , formulation ) capsule
each . * to * , but a causal relationship to the study study the to relationship a causal , but ) abnormalities test laboratory including * ) subjects ( tablet/
[ ( capsule ty severi in mild all subjects 7 ( , events] after the administration of the tablet tablet the of administration the after events] 3 (median, 3.0 hours) compared to the capsule capsule the to compared hours) (median, 3.0 its 90% confidence interval w interval confidence 90% its There were no deaths, serious adverse events adverse serious no deaths, There were
1 subject 1 subject
7 ( .
ratio events adverse serious l of 7 days , which were both classified as adverse drug drug as adverse classified both were which , max adult adult healthy foreign in
) , t
events] after the administration of the capsule the capsule of administration the after events] ∞ with
0- 37 3 subjects ratio ratio nasopharyngitis subjects [ subjects
, P0065.3.1.2.1 shorter (
5 . relatedchanges of formulation n,
- max ; As to clinical laboratory values, values, laboratory clinical to As events , or adverse ) ). subjects [ subjects ”
study crossover study study crossover
2 ( dosein 2 including laboratory test abnormalities test laboratory including - .
( al relationship to the study drug could not be denied could be drug not study the to al relationship
influence treatment
and the C
). the of Sitagliptin as either the capsule formulation or the tablet formulation formulation tablet the or formulation capsule the either as Sitagliptin of period,
events] after the administration the the capsule formulation of events] after administration events] after the administration of the tablet formulation tablet the of administration the after events] ed administratio ed ] 1.07 f 5 hours 2
; clinical adverse events occurred in occurred events adverse clinical and of the tablet formulation tablet the of and changes or changes label, 2- clinical adverse events occurred in in occurred events adverse clinical 1.02, ommonly reported adverse event after the administration administration the after event adverse reported a commonly was ache [ 13 3
analysis showed that showed theanalysis AUC , subjects [ subjects adverse drug reactions subjects [ subjects
stomatitis
“ , or adverse events events adverse or , Head 1.04 ) 4 s analyse safety and the in pharmacokinetic included were subjects treated 2 median, 4.5 median, , ( ( ). ; slightly slightly a had formulation tablet Formulation comparisonFormulation ) formulation were 2 after the administration of the tablet formulation tablet the of administration the after
(
The . 24 hours post up tohours 24 observed .A.
single 50 mg oral dose of
rmulation
harmacokinetic including laboratory test abnormalities test laboratory including abnormalities Regarding safety, safety, Regarding extrasystoles no deaths were There all events. for denied was drug findings physical and ECG, signs, vital values, laboratory clinical to respect With meaningful clinically to was investigate conducted of Sitagliptin the pharmacokinetics A period a washout by separated administered, to be was formulation capsule the of administration formulation formulation 1.33]
12 the of All P fo 4.(i) open- randomized, A safety Regarding formulation events] subjects 4 in reported headache interval formulation adverse events for which a caus which for events adverse to as referred was was reactions, but were not serious, requiring no treatment requiring serious, not were reactions, but capsule capsule ( . to discontinuation leading
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page38
, 1 ) to of in the ***** period serious serious , *****, or 3- ***** after the included in in included dose dose s were 1.05 s were
and and
all all label, . vital signs, and ***** oral
light headedness events] after the , events] events] or placebo were Reference data , Reference 5 an ] were were day washout period ) ( ***** - and
) 8
5
a
) including laboratory test
le subjects le subjects fema and male ( . * 20** 100 mg were included in the safety inthe safety included were , subjects [ tablet formulation containing containing formulation tablet ) There were no deaths no were There tablet formulation containing formulation tablet each Part each to * ( headache 3 confidence interval confidence .
were similar between the two two the between similar were (
subjects [ to be given
in the
1/2 50 mg *** 4 t [ , 90%
ratios subjects were
and a randomized, open - and a randomized, , and there was and subjects ) ) 12 Reference data , Reference max Of which,
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25 mg 5 *****; max 10 t tablet formulation containing formulation tablet events adverse or , dose ( ) Part
20**] (
and C the
∞ The * *
corresponding corresponding 0- , 5.3.1.1.2 [ 38 of Sitagliptin of .
male and female subjects were conducted to evaluate toevaluate conducted were subjects female and male
of tablet formulations containing formulations tablet of with P027 intravenous adult With respect to respect clinicalWith laboratory values subjects; Part II, blind study - . day washout interval between the two periods the between washout interval day an
10 7- or adult adult healthy foreign in study crossover , healthy healthy ],respectively
, 5.3.1.2.2 (
Part I, bioequivalence bioequivalence . changes related (
1.22
after the administration of of [1 administration event]the after were classified as adverse drug reactions drug adverse as classified were of Sitagliptin as either as Sitagliptin of
period, ) fat meal there was a there foreign 2- tablet formulation containing of containing the formulation tablet the administration after event] - 1 tablet formulation containing containing formulation tablet in , 0.94 ( of Sitagliptin doses le intravenous controlled, double [ and ) clinical adverse events occurred in occurred events adverse clinical subjects who received Sitagliptin received who subjects tablet formulation containing *****). containing formulation tablet label, a high the sing
20 13 1.07
Part II , including laboratory test abnormalities test laboratory including (
(
leading to discontinuation to leading after subjects treated
.
) and . analyses safety and the in pharmacokinetic included were subjects treated . light headedness light or
s Bioavailability and food and Bioavailability study ( effect Bioequivalence study Bioequivalence . th mild in severity in mild th escalating ofwhich ) ) 4 3 macokinetic analysis. analysis. macokinetic had bo ( ( 1.07] tablet formulation containing *****) containing formulation tablet - drug no study , there were .A. .A. 100 mg of single 100 doses II, and in Part given
harmacokinetic analysis showed that the AUC the that showed analysis harmacokinetic 1.02, [ headache had 1 subject was to be administered administered to be was fasted state state fasted ECG [ between doses between be Sitagliptin abnormalities All of the 22 the All of events adverse In Part I, 4.(i) placebo- randomized, A *****, Regarding safety Regarding of administration the of administration ( P *****/ effect and food ) formulation (tablet Sitagliptin of bioavailability absolute the All of the 12 the of All establish the towas establish conducted mg of 100 dose oral single A 4.(i) open- randomized, A formulation the phar analysis, analysis, subject subject crossover study crossover
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page39
, ] n ] i max the and and 249 C , ), 1.62 PartI, In Part Foreign spotting spotting was was ). and in
asked the the asked ) , 1.110.97
acceptance acceptance Only male male Only ∞ R leading to
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( , P076 dose proportional, - AUC menstrual menstrual 1.37 including laboratory minutes sampling points sampling ranges acceptance the arithmetic mean arithmetic
dose ( geometric mean ratios ratios mean geometric geometric mean ratios ratios mean geometric , 25 mg
[ 1.03 s were and
25 L arithmetic mean arithmetic
a
after a meal observed in in observed after a meal ( ] All of these of All was was
bioequivalence bioequivalence , nausea
max max ). C C 262 max fter fter minutes prior tominutes the scheduled 1.02 and a Japanese Study Study Japanese C to ( 0.828
and and
clearance the renal to ∞ n Study P076. PMDA P076. n Study ∞ , but , but P029 in Study than were lower i
0- 0- ), , 0.94 [ idence interval idence pharmacokinetic pharmacokinetic , of Sitagliptin Sitagliptin of
0.654 subjects fell within the the within fell
∞ conf 4 0- of increased increased of ( events adverse , serious was
in the fasted state were similar to those after a a after tothose similar were state inthe fasted geometric mean ratio (fed/fasted) following a ratio following mean (fed/fasted) geometric
) in Part II, headache Partin II, 90% ∞ -
1/2 max
t dizziness in Part I, tablet of Sitagliptin was given to Japanese subjects subjects Japanese to given was Sitagliptin tablet of
e, 0
effect deaths
0.98 s were ell within the bioequivalence bioequivalence the within ell f 39 geometric mean geometric ( ( dose and as breakfast at about 30 about at as breakfast mg range acceptance
dose including laboratory test abnormalities test laboratory including exclusion criteria exclusion ( max 50-
/ for the C the for were classified as adverse drug reactions, but were mild in in mild were but reactions, drug as adverse classified were a
in Part I, the AUC in I, Part style meal and the AUC and meal style and the mean age and BMI age mean and the , 100 mg s consumed completely within about about within completely s consumed ns conditio these under clots
intravenous a
421 mL/min and the t and the
inclusion the volume of distribution was 198 was of distribution volume the , max oral dose both f oral both dose with corresponding ) with given to foreign subjects in the fasted state or after a a or after state fasted fthe Sitagliptin in subjects toforeign was given to
), by PMDA fter fter Japanese and foreign clinical studies ( studies clinical foreign Japanese and bioequivalence bioequivalence a confidence interval confidence mg ;
a meal was served was a meal - 413 sporadic andC 100 mg , fasted
, P076 in Study the / , factors ∞ a tablet o tablet
0- 90% was fed a 100 confidence interval confidence )
mg fter the 90% confidence intervals for the AUC for intervals confidence the 90% clinical adverse events occurred in occurred events adverse clinical p , respectively , a
events adverse , or
AUC
; 6 Cl their drowsiness (
100- , 90%
, hile geometric mean geometric he 1.03] ( a
T clots W
fell outside fell
f dose excreted unchanged in urine inurine unchanged excreted fdose . . the In both studies In
with . following .
, hand the other
) , 0.86 [ , events adverse laboratory no were There Outline of the review . On dose ) P029 .
s sporadic fatmeal fat meal fasted - - 0.94 .B / menstrual spotting with spotting menstrual mg 340 mL/min fed with with potential potential the and its reason to explain applicant increased hunger increased , P029 Study the fraction o fraction the for for severity ) abnormalities test . discontinuation (fed/fasted) ( 50- - Japanese a after or state fasted inthe range to geometric mean ratios ( ratios mean geometric and The applicant responded as follows: as responded The applicant . subjects Japanese , P029 Study In high Study Study
Food effect in evaluated was effect Food 4.(i)
analysis to pharmacokinetic According high safety Regarding plasma clearance clearance plasma respectively time of drug administration and wa administration of drug time of Sitagliptin after oral administration was 87% was administration oral after Sitagliptin of bioavailability the absolute II, P076 Study into enrolled were subjects background subject other
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page40
, a the by
, and was ”
were there
P013 , ( max
partially partially C based on the the on based
Sitagliptin activity C Notification No. No. Notification criteria of 4 Japanese and and Japanese is expected to to expected is - due to the Interaction Studies Interaction observed in Study inobserved Study 813 dated June 4, 2001]) 2001]) 4, June dated 813 DPP
. Meanwhile, in some drug drug some in Meanwhile, . 2 [PFSB/ELD -
Although the definite the Although definite max ” ). 0.5 acceptance acceptance as
the had specified the range for Sitagliptin P003
(
) state fed inthe
Methods of Drug of Methods “ efficacy and safety safety and efficacy in Japanese clinical studies clinical inJapanese
applicant As to the background factors background the to As subject background background subject
because but accepted the applicant’s response . elderly
SB/ELD Notification No. Notification SB/ELD the increased C the increased ting of Generic Drugs 500 nM F P [
” the notification notification the effect, ied by the applicant. In evaluating drug interaction, PMDA PMDA interaction, drug evaluating In applicant. the by ied the of percent inhibition confirmed specified range for Sitagliptin pharmacokinetic studies or studies pharmacokinetic Sitagliptin for range specified - female and elderly subjects who have been shown shown been have who subjects and elderly female
han in thehan - non 40 differences in the differences has been been has the discussion on the the on discussion the Interaction Studies Interaction
) the om the pre the om , state fasted inthe
ncluded er values,er taking intoaccount the efficacy and informationsafety from the relevant Guideline for Bioequivalence Tes that the differences in the results between between inthe results that the differences “
i P029 clinically meaningful meaningful clinically 366 nM Methods of Drug of Methods “ that that and Sitagliptin of pharmacokinetics the on effect little
Study Study , is only unknown P076 in Study
associatedwith had possibility , taking account of
max
] and the the ]and
C should have no potential for for no potential have should study effect food Japanese the in observed 1 is considered important for assessing the clinically meaningful effects of of effects meaningful the clinically assessing for important considered is
BMI effect excluded, be not can P003) Study values in
max in Study P076 ( P076 in Study
max ). that that analyses, and clinical efficacy/safety profile of Sitagliptin and the the and Sitagliptin of profile efficacy/safety clinical and analyses,
max C , which increased increased 1 A202 , the
; higher C databased theon bioequivalence acceptance ranges as specified in Japanese healthy adult male subjects adult male healthy Japanese considers considers that the
the A112 should have no potential for a potentialno for have should , t for AUC t for The applicant explained that the most relevant pharmacokinetic parameter to assess a clinically meaningful change is AU
clinically meaningful meaningful clinically studies. on clinical based that the increased C increased the that P076 P076 1 achieve almost maximal efficacy based on the on data efficacy maximal almost achieve studies the between similar were etc. subjects of management the are data showing are data were studies clinical foreign (e.g. conditions study different to exhibit Sitagliptin reason for the for reason higher in females than in males and in the elderly t elderly the in and in males than in females higher mode of action, PK/PD me Sitagliptin; and the safety of Sitagliptin up to 200 mg (Japanese type 2 diabetes mellitus patients) or or patients) mellitus diabetes 2 type (Japanese mg 200 to up Sitagliptin of safety the and Sitagliptin; ( mg 400 PMDA pharmacokinetic studies for lack of a clinically meaningful change for the AUC geometric mean ratio mean geometric AUC the for change meaningful clinically a of lack for studies pharmacokinetic interaction studies etc., other bounds that are different fr bioequivalence acceptance the in ranges specified (as A111 1124004 dated November 24, 2006 24, November dated 1124004 were set forassessment. checked PMDA the rationale for these ranges specif assessed study and other clinical studies, etc. made inquiries about individual deviations of the paramet the of deviations individual about inquiries made
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page41
, is to
M) the the 100 100 was
) , P034 ),A203 and
When the 4.2.2.4.4 - P031 CYP3A4 ). 10 μM inhibited inhibited ( The potential - A201 gliptin uptake uptake gliptin
. ( were all > all were
the results from the from results ita ) CYP3A4 mRNA S
cimetidineuptake and inhibited the andthe inhibited , P026 -
, H uptake of Sitagliptin of uptake 3A4 3 activity , , was investigated. As a a As investigated. was
) 6, to 4.2.2.3. was about 38%was values for of Sitagliptin P025
, respectively , 2D6 ) had no inhibitory effect on effect inhibitory had no of Sitagliptin of mediated mediated inhibitor, gp 50 - - ) and it was inferred that blood blood that inferred it was and diabetes mellitus diabetes , P022
, 2C19 3 4.2.2.3. , a P in vitro in was observed and Sitagliptin was was Sitagliptin and observed was
, 1.21 . The IC
hO AT3
, , and hPEPT1 Sitagliptin treatment (1 and 10 μ treatment Sitagliptin 500 μM . at at concentrations of 0.1 to 500 μM M , , P018 As the reference data, the reference As 2C9 μ was was and M5 . , 0.3-
78.6 78.6 , and μM ) (
for lines other cell
hO AT 4 nd transport , 4.2.2.3.1 200 2C8 a patients with with patients ( , P017 11.1 yclosporine
, , and hO AT3 in vitro in , - 0.02 . C , 6.2
( 2B6 100 100 μM 1.1 μM ofvalue 1.1
,
,
, P014 M 41 Sitagliptin 50 μ or . the transcellular transport transport transcellular the 2.2 5 , directional directional were submitted were
were investigated were gp human liver CYP3A4 of human inhibitor hO AT 3 10 - ) . The microsomes and hepatocytes in human studied was
. , gp verapamil, ritonavir, and vinblastine and ritonavir, verapamil, P , P012 - ) - 1.7, , 0.1- CYP1A2 M ( Sitagliptin Sitagliptin (
P046
μ ( 3.7,
P007 with an IC an with hO AT 1 human human 10 ,
( substrates substrates dependent
digoxin As a result, As evaluated. was hepatocytes in human -
the ults from Japanese phase I clinical studies in healthy adult subjects adult healthy in studies clinical I phase Japanese from ults dependent, uni isoforms , P005 -
cidofovir uptake, but it showed weak inhibition of of inhibition weak showed it but cidofovir uptake, - using human biomaterials hOCT2 H of Sitagliptin Sitagliptin of plasma clearance plasma time
3 hOAT1/ 3 - P001 the res the Sitagliptin - , values of 5.6, of values The main study results are described below. described are results study main The
. C
50 studies 14
Japanese phase II clinical studies in studies clinical II ), phase Japanese )
; hOAT3 K1expressing cells IC cells expressing human P human expressing cells -
). plasma ratio plasma A112 plasma protein binding of binding protein plasma n vitro , with PK1 I ( -
is partially involved in the formation of M2 of formation the in involved partially is t of transpor mediated -
1) for CHO for (
A111 Summary of the submitted data submitted the of Summary a substrate of of be a substrate to considered was Sitagliptin LLC gp - , mediated transport of Sitagliptin transport mediated = 160 μM human human - P time a not was and Sitagliptin Summary of clinical pharmacology studies of clinical pharmacology ) Summary
50 ii gp ( - M 10 μM , P013 IC result was inhibited by probenecid, ibuprofen, furosemide, fenofibric acid, quinapril, indapamide, and and indapamide, quinapril, acid, fenofibric furosemide, ibuprofen, probenecid, by inhibited was cimetidine ( results demonstrated minimal metabolism of Sitagliptin and it was considered that that considered itwas and of Sitagliptin metabolism minimal demonstrated results were submitted ) were P037
( ssingexpre lines cell Using 4.(ii).A. As As the data evaluation 4. human liver microsomal CYP liver microsomal human of Sitagliptin to induce CYP3A4 induce to Sitagliptin of to in response activity were not affected and enzyme expression ( 4.(ii).A CYP2C8 primarily involved in the formation of the metabolites of Sitagliptin, i.e. M2, M5, and M6 and M5, and M2, i.e. Sitagliptin, of of metabolites the formation in the involved primarily The metabolism of The metabolism 9 4.2.2.4.6, 4.2.2.4. The and a Japanese drug interaction study interaction drug Japanese a and effects of Sitagliptin on Sitagliptin of effects μ human blood/ human foreign clinical studies ( studies clinical foreign Sitagliptin did not inhibit inhibit not did Sitagliptin will approximate will clearance Using investigated. As a result, result, a As investigated. for for toconsidered be a substrate the transport of quinidine by about 30% at 500 μM P
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page42
) ] ]
*
, 50 dard to be CI]
mercial mercial
and this and this between 1.05, 1.19 1.05, 1.00, 1.39 1.00, [ [
% 95
ere [ per panel per Mean ratio Mean w 12.5 mg 12.5 1.12 1.18
mean of fraction of subjects
dose study in in study dose .
cases
interval
male ) dose proportional doseproportional )
8
6
squares s subject to active active to subject s - 5 = in a dose escalating
, Period 2, Period 3, 3, 2, Period , Period Fed 171 391 11.8 2.23 **] 100 mg 100 n 513 mL/min , 0.856 25 mg ( The mean fraction of of fraction mean The than than week week least . Sitagliptin Sitagliptin to 17 subjects excluding 1 1 excluding subjects 17 1-
escalating escalating
* 20 and
) a
6 ,
299 2 = Period 1 of Sitagliptin of ases of 16; ases
513 32.0 9.07 1.00 greater greater 3950 n to * arithmetic Fasted ( 400 mg 400 ; least least single single
was 1/2 * *
of which t Japanese healthy adult
administered after a stan a after to be administered 25 mg
R suggested thatSitagliptin has no [
)
, respectively 3,
6 or of placebo , for for
)
Cl 3 = s 6.5 slightly slightly
475 1 9.14 was was M 1970 n 0.954 panel, panel, Fasted
( P013 200 mg 200 μ , , and 400 mg 5 mg
ina
10 with increasing dose with increasing
)
(
There was at was There 6 of Sitagliptin to Sitagliptin of
25 mg
indicating that Sitagliptin i Sitagliptin that indicating arget number of c of number arget . s 2 = 1/2
t 959 415 t
8.65 9.56 , ( n harmonicmean 0.878 Fasted
(
100 mg 100 ; Number Number
, 200 mg
and the mean the mean and max 42
and increased increased
) Sitagliptin Sitagliptin
6 single oral, single dose
1.0 max 2 = max
309 464 t or 11.4 3.76 adult subjects ng manner ng -∞ n 0.851 blind, crossover C 50 mg Fasted
to ( i single oral dose
- , Period 2, and Period
e,0 , 100 mg f median for t bo
; for for
R
)
6
Cl 5 =
397 149 , Study , Study 5.3.3.1.1 11.6 2.04 n 0.787 25 mg ( , 50 mg Fasted ( Period 1
and Pharmacokinetic and food effect study of the proposed com proposed of the study effect food and Pharmacokinetic
of place of in state in the fasted be administered to in max
1)
( s C
) a dose escalata dose
, 6
glomerular filtration rate filtration glomerular ere . 4 = 0-∞ , 25 mg .A.
445 59.4 12.3 ) w n 0.960 0.850 i Fasted ( the safety, tolerability, pharmacokinetics, and pharmacodynamics of single of single pharmacodynamics and pharmacokinetics, tolerability, safety, the
12.5 mg ( controlled, double
AUC proportional and the
male subjects living in the US the in living subjects male )
)
for
6 typical
ee “4. = 6 assess
fasted CYP3A4 s , 12.5 mg / 400 mg 299 n
26.9 13.8 [ 5 mg adult ( 0.499 0.730 Fasted
the mean
. fed Pharmacokinetic parameters following parameters Pharmacokinetic (
s
. Pharmacokinetics in healthy , analysis safety inthe included were subjects treated 4 and io uman pharmacokineticsuman
- dose was re was a trend towards shorter towards a trend re was
,
1) H ∞ . 18 )
squares
- 0- h style breakfast in Period 4. In Panel B Panel 4. In Period in breakfast style healthy healthy · Table ) The 2) placebo or Sitagliptin Sitagliptin or placebo of oral dose a single and .
(2) ( secretion M , .
μ least ) (
AUC 200 mg ∞ , respectively, in respectively, 4, Period ) nM ) 0- ( Phase I single oral dose study dose oral single I Phase h mL/min ,
Parameter h
( (
( ∞
- R max eometric mean rat e,0 max 1/2 4.(ii).A. potential to induce 4.(ii).A. dose oral Panel single A, In - Japanese mg and administered in the state administered fasted dose excreted unchanged in urine was 0.73 urine was in unchanged dose excreted tubular The All of the the All of
and pharmacodynamic pharmacodynamic and in pharmacokinetic the included were Sitagliptin receive not did subject who analyses A randomized, placebo- randomized, A (a) (a) rifampicin control positive the with and comparison was was conducted to manner oral doses of 5 mg of oral doses manner value exceeded exceeded value 4. Table in presented are parameters Pharmacokinetic Japanese Japanese dose escalation dose eometric C t t f Cl AUC G G * dose excreted unchanged in urine extrapolated to infinity to extrapolated urine in unchanged excreted dose
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page43
a In of of 40
the
100 was was
s were , ) group 10. on the on the 50 - )
otal
t
mg until the the until , time ) 50 mg EC . parameters 50
of **] , multiple oral oral multiple 6.5
( tions and the the tionsand parallel the
activity in a a in activity ta after Day 9) panel] , of mg ,
, but their causal , their causal but 4 - 25
cases per panel per cases from Day 4 to * * 20
As laboratory adverse adverse laboratory As laboratory times the ULN times days and days model . )
. concentra
increased 10 5
Of which, 3 events of of which, 3 events Of from Day 1 to Day Day from max .
20** E . AST * * about about
), ( There were no deaths or serious serious or deaths no were There [
anel hours later hours
was discontinued was Sitagliptin Sitagliptin subjects of Sitagliptin in Period 1 or Period of in Sitagliptin of Sitagliptin in the morning in the the in theof in morning Sitagliptin
12 A111 subject dose escalation dose subject was not reported not was oglycaemia 12 - , analysis safety the in included were increased in p each In this subject, all all subject, this In ) placebo [2 subjects in each ineach [2 subjects placebo
]
inter treatment treatment orally receive Sitagliptin receive orally .” in the fasted state fasted inthe
as consent was withdrawn after study drug drug study after withdrawn was as consent GTP ) and hyp panel and γ
panel,
sted and state sted was to 43 5- unlikely arget number of cases of 50, of of cases number arget “ t of Sitagliptin once daily for 10 for daily once Sitagliptin of , and treated with treated (
plasma Sitagliptin trough concentrations reached reached concentrations trough Sitagliptin plasma blind, blind, - in Period 2 in Period in the morning the in
activity was analyzed using an using analyzed was activity , Study Number Number , Study 5.3.3.1.2 200 mg subjects subjects were classified as adverse drug reactions drug as adverse classified were (
4 , each subject , subject each -
10 hour washout period, and then receive multiple oral multiple of0 mg 5 doses and thenhour washout receive period, D and - nce subjects received placebo received subjects 8 subjects in each ineach subjects 8 .
, times the upper limit of normal [ULN] normal of limit upper the times DPP
otal otal subjects t male t and 6 once daily receive a single oral dose of 50 mg dose oral a single receive ( Two , days , . C
in the morning in the fa in the morning the in the subject had no pharmacokinetic or pharmacodynamic da pharmacodynamic or pharmacokinetic no had subject the ( ,
somnole When the relationship between plasma plasma between relationship Whenthe 100 mg
about twice the ULN) the twice about B . controlled, double . about about clinical adverse events occurred in in occurred events adverse clinical , ( ( ,
was to was
Sitagliptin [ Sitagliptin and oral dose study A
the safety, tolerability, pharmacokinetics, and pharmacodynamics pharmacokinetics, tolerability, safety, the a 72 , undergo h 26 . discontinuation drug after study normal to returned 50 mg
including laboratory test abnormalities test laboratory including , , respectively , Panels Panels assess subjects treated increased increased
multiple GTP headache subjects excluding 1 subject ( in B Panel excluding subjects / γ 50 in 1 subject at 1 week after the administration of 5 afteradministration themg 1 week at 1 subject in
treated wit treated hip to thestudy drug wasjudged as , each subject subject each , ALT ALP 49 E
dependent manner dependent - Phase I Phase , or 200 mg successive successive nel
( events adverse except for for except following day of placebo administration placebo of day following of Sitagliptin twice daily twice Sitagliptin of observed relations Pa 1 in Part state fasted 2 13 in Part of Day morning ULN), events, events, which 8, Day on administration subjects subjects . analyses and pharmacodynamic inthe pharmacokinetic included were mg percent inhibition of plasma of plasma inhibition percent drowsiness , analysis to pharmacokinetic According the All of In (b) (b) - placebo randomized, A dose 10 for daily twice Sitagliptin Pharmacodynamic analysis showed that Sitagliptin inhibited plasma DPP plasma inhibited Sitagliptin that showed analysis Pharmacodynamic ] formulation commercial proposed the of pharmacokinetics the for formulation” 26.2 nM 26.2 be to estimated Regarding safety, safety, Regarding conducted to to conducted study in Japanese healthy adul healthy Japanese in study doses of 25 mg of doses
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page44
, . , 1 1.03 state state With With were With arget - t ) . . ( model
including including increased ( Sitagliptin The mean mean The max .
E a . . ) TG There were no no were There post procedural procedural post regimens , sm . 1.05. eosinophil count count eosinophil , . changes related - ly glucagon 20**] dose on Day 10 were 10 were dose on Day using an 10 days dai * - there are no clinically clinically no are there - or , was not reported was not 10
increased (Day 10/Day 1)was
headache to ** , administration, the percent percent the administration,
events adverse or , ALT . was 355 was mL/min ratio peptide, *** ) subjects ( - R [
Of which, only which, Of
24 /Day 1) was 10/Day 0- 25 nM 25 about tobe estimated was ). myalgia
( 50 A112 . daily and twice and daily subjects in the Sitagliptin group Sitagliptin the in subjects repeated - 8 subjects
events] 5 2 on Day 1 and Dayon Day inhibition was comparable between Day between comparable was inhibition
[ ratio (Day ratio(Day subjects subjects daily daily dependent manner, but the percent inhibition inhibition percent the but dependent manner, 4
- - 3 adult adult in healthy 24 and the EC and the s, and s, and pharmacokinetic tolerability, safety, the and the mean Cl the mean and 0- The mean fraction of dose excreted unchanged in in unchanged excreted dose of fraction mean The
of Sitagliptin once daily for for daily once of Sitagliptin 395 mL/min once levels at post 4 and 24 hours 10
1
44 - to When the relationship between pla between When the relationship occurred in occurred assess
. was 0.73 was analyzed was
was classified as an adverse drug reaction drug adverse as an classified was occurred in in occurred subjects male adult healthy Japanese in study blind - orally administered once daily in the morning in the fasted fasted the in morning the in daily once administered orally proportional and the AUC the and proportional
was 355 was R , Study Number Number , Study 5.3.3.1.3 active GLP active ( insulin, glucose, blood prandial C Cl - to be , group placebo the jects in administration in both both once in administration Day 1 and DayDay
inhibition 4 including laboratory test abnormalities test laboratory including sub - dose was It was determined that that determined was It - post was ( eosinophil increased count leading and hypoglycaemiatodiscontinuation leading 2 mean mean
24 or prandial (
- - in a dose increased activity 0- DPP was conducted to was conducted 4 between between repeated repeated -
in urine unchanged s controlled, double administration and the AUC the and administration , post of 400 mg
and the 10)
in the 100 mg group 100 mg the in laboratory adverse events adverse laboratory oral dose study dose oral ) events adverse clinical plasma plasma , each] vent 5 e
3 0.81 , 1 . Day2 [
and difference repeated ly dosing
treated subjects subject ) by multiple effects on fasting on fasting effects no days of 1 dai
( -
10 events adverse serious . accumulation of evidence no therewas and ere state state
- increased daily dosing, the AUC the daily dosing,
- Phase I Phase 1.19
) abnormalities test laboratory increased respect to vital signs and ECG, there were no clinically relevant changes or treatment or changes relevant no clinically were there ECG, and signs to vital respect , deaths CPK complication meaningful safety Regarding With once With . levels baseline the than higher , with analysis to pharmacodynamic According number of cases of of of cases number
steady a reached concentrations trough Sitagliptin plasma that showed analysis Pharmacokinetic by Day 2 DPP plasma that indicated analysis Pharmacodynamic - placebo randomized, A (c) steady once fraction of dose excreted excreted dose fraction of to there w there Sitagliptin or Placebo 400 mg of 400 oral doses of multiple pharmacodynamics state for state analyses and safety pharmacodynamic, thein pharmacokinetic, included 10 the of All to 0.71 was urine inhibition of plasma DPP plasma of inhibition was similar between Day 10 and Day 1 Day and 10 Day between similar was concentrations and concentrations
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page45
, ] (1 the
was vity vity ) 20** labeled labeled - including including dose C **
( there were
* 14 , ce data to group only group investigate of radioacti . There were no
*** [ of the radioactivity radioactivity the of
Referen dioactivity dioactivity 1 subject with a low low a subject with 1 ,
d. With d. With reporte was not 400 mg 400
P032 **] up to the last measured last measured theup to were reported. reported. ) were
of the oral radioactivity dose dose radioactivity oral the of
, respectively, , events adverse or , a single doseof asingle )
of which *** 20 the oral ra oral the 6% (AUC indicating that the major pathway that the pathway major indicating 79% -
,
of
last 1% ** to . 0- the Sitagliptin Sitagliptin the administered and blood, urine, and and urine, to blood, and be administered 87% crossover study in foreign healthy adult adult healthy in foreign study crossover M3 and
. However, as the the as However, . analysis pharmacokinetic of the oral radioactivity dose was recovered recovered was dose radioactivity oral the of *** 20 Six metabolites were detected and the most the most and detected were metabolites Six 7% ry [ - , and . samples collecting when a problem . % period, Approximately Approximately
effects on fasting blood glucose in healthy adult adult healthy in blood glucose on fasting effects 4
(
of Sitagliptin after Sitagliptin of P009
, M4 , Study Number Number , Study 5.3.4.1.1 prima 45 observed in observed (
M2 , M1 was parent compound accounted for 74% for accounted compound parent Approximately Approximately
Sitagliptin in this subject was similar to those in in those to similar was subject this in of Sitagliptin 100 mg in feces. feces. in
ed Sitagliptin was was Sitagliptin ed . relatedchanges .
and - M6
. the last interval
0- controlled, 4- label - including laboratory test abnormalities test laboratory including dose ( - C QTc 14 including laboratory test abnormalities test laboratory including usal relationship to the study drug was denied was drug study the to relationship causal its but of (
, leading and hypoglycaemiatodiscontinuation leading ) effect on on effect , Study Number Number , Study 5.3.3.1.6 blind, placebo- blind, ( - clinical adverse event adverse clinical the a
study ) and radioactivity AUC radioactivity and
treated subjects were included in the safety analysis, analysis, safety inthe included were subjects treated There were no clinically meaningful clinically no were There )
6 , analysis to pharmacokinetic . label study in foreign healthy adult male subjects was conducted to conducted was subjects male adult healthy inforeign label study
and other metabolites included ) and other metabolites included ADME Oral Oral Study assessing Study
) abnormalities test laboratory findings and physical weight, body ECG, values, vital signs, laboratory to respect clinical treatment or changes relevant no clinically events adverse serious deaths, subject, 1 eventinjury of limb the from excluded was radioactivity of recovery of readministration following rate recovery been there had that inferred was it 5 subjects, the other concentration Sitagliptin mg 83.04 of dose oral single A A randomized, double randomized, A (e) According All of the the All of
(d) (d) open- An safety and balance, mass pathway, elimination post week 1 for collected were feces data Reference
. subjects safety, Regarding . 10 and Day in plasma, as determined by the ratio of Sitagliptin AUC Sitagliptin of the ratio by as determined inplasma, was recovered unchanged in urine and approximately 16% approximately urine and in unchanged recovered was dose of dose in the in urine, 3% of feces) (13% the as metabolites abundant metabolites in plasma were M5 were inplasma metabolites abundant and approximately 13% approximately and urine in recovered of elimination of Sitagliptin is via urinary excretion urinary via is Sitagliptin of elimination of in plasma events no adverse safety, Regarding
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page46
, , ee ** 79 At
M s and * . [ n . [ ALT mean mean 3.7 ms 3.7 100 mg 100 100 mg 100 100, ), 2440 2440 A202
) A203 , intervalwas which of ( ± events were were events 50,
there was no no was there , , of Sitagliptin on on Sitagliptin of 25
026 QTc 20**] No serious clinical weeks Sitagliptin Sitagliptin
dose was 8.0 ms was dose - 4 *** and ) were and 882.8 3 hours to positive control positive
; (
from baseline was was baseline from ) Sitagliptin Sitagliptin . of Sitagliptin of SD
] ;
± ) 20** hours and 10 hours hours post hours A202 * and safety analyses, analyses, safety and ( 2
There were not any differences in in differences any not were There ** A201 mean mean . [ ( subjects, of which 40 (
max moxifloxacin moxifloxacin change from baseline across the 2 doses doses 2 the across baseline from change 42
day washout interval between periods between washout interval day 10 ms A201 group, comparative studies in Japanese Japanese in studies group, comparative weeks - llitus me 2 diabetes QTcF ) and C
from baseline at 3 at baseline from
46 ) ]
median , the mean change in QTcF inQTcF change mean the , , mg the of 800 a dose following while maximum . ) ( aboratory adverse events occurred in 1 subject ( subject 1 in occurred events adverse aboratory , QTcF max , or placebo, or orally administered for * 20** dose - it will be less than than less be it will , Study Numbers 3, Study Two l - controlled, parallel were conducted to evaluate the efficacy and safety of Sitagliptin of Sitagliptin safety and efficacy the evaluate to conducted were for the study design and safety data and safety design study the for . daily
” - to ** sitivity of the assay to detect modest increases in increases modest todetect theassay of sitivity twice hour post hour
. reactions drug adverse as classified were which , 5.3.5.1.1
) ( 1
( at any time point time at any The sen *** 20** ies [ corrected change in change corrected 50 mg - clinical adverse events occurred in in occurred events adverse clinical - placebo blind, - increased diabetes mellitus diabetes A203 Sitagliptin, or placebo and there was a 7- was there Sitagliptin, and or placebo , observed
, nor any differences in the maximum in the , nor any differences maximum **] AST Pharmacokinetics in patients with type type with patients in Pharmacokinetics respectively, at a dose of 100 mg of Sitagliptin and of Sitagliptin mg 100 of at a dose respectively, treated subjects were included in the pharmacokinetic pharmacokinetic the in included were subjects treated
. , Sitagliptin Sitagliptin QTcF placebo orally administered once daily for 12 once daily administered placebo orally the primary hypothesis that hypothesis the primary 2) .
QTcF 86
Phase II clinical studies clinical II 2) Phase 800 mg , 800 , M ( or placebo orally administered once daily for weeks 12 daily once administered orplacebo orally n or with type 2 type with *** 20
(2)
.A. ) daily - interval iii PhaseII clinical stud
207.7
4.( once “ 200 mg 200 ±
4.(ii).A. (a) 20** to double Randomized, patients 100 mg
that the t the that showed analysis Pharmacokinetic
mg 400 either of dose oral single a of Each consisted period s dose of single effect potential the toassess conducted was subjects female and male QTc Sitagliptin the All of subjects excluding 7 subjects who completed < 2 periods of the clinical study were included in the the in included were study clinical the of periods 2 < completed who subjects 7 excluding subjects . analysis pharmacodynamic increase in increase . moxifloxacin control positive the with established 100 mg of 100 a dose following analysis, to pharmacodynamic According respectively, at a dose of 800 mg of Sitagliptin mg of 800 dose at a respectively, reported. reported. were events adverse classified as adverse drug reactions drug adverse as classified and increased increase in the placebo the in increase supporting maximum . and placebo ofSitagliptin 77 safety, Regarding the prespecified time point time point the prespecified
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page47
, ,
] the 23 23, ]
dose
.6 - ) ) ) ) 64.3 were
[ ) 50 mg
66 67 77 68
474
and and , 232.7] , = = = = , 1050.2
, 5.3.3.5.2
( n n n n 219.9 446.0 980.8 ] activity at at activity Treatment Treatment
( ( ( ( 2058.1
hours post hours 4 207.9 419.1
915.9 [ [ at 67.3% - 1898.0, 2231.7 ] [ [ 2.5 ] 106.3 , A203 Study In 177.3 Treatment Week Week Treatment
[about 20% [about ollected over time time over ollected
dose were at -
54.0, dose [ - Reference data Reference ) ) ) )
old healthy subjects or or subjects old healthy 136.7,
, - [ dose 66 67 77 68
1257.4] -
, 237.3] , 536.5] = = = = The percent inhibition of inhibition of The percent
nM and Sitagliptin at ≥ at Sitagliptin and n n n n 217.9 492.4 . 1149.9 ( ( ( ( 2507.0 year
nM P033 A202 hours post hours 200.1 452.0 ,
12 [ [ atpre Blood was c Bloodwas 2199.1, 2857.9 ] 1051.6,
[ [ concentrations following a 100 following concentrations 80-
dose 1.5 The percent inhibition of plasma plasma of inhibition percent The
- sampling points sampling to 12
P029
- in the 100 mg once daily group and and group once daily mg thein 100
at 24 hours post at 24 hours
]
. group . A202 Study of group 18 confidence interval confidence
) ) ) ) dose
-
ns in Study 66 66 77 68 10 119
] 82.2 P027, , , 217.0] , 508.0] = = = = , 1266.7
Sitagliptin Sitagliptin , the percent inhibition of DPP inhibition percent the n n n n 191.6 443.1 95% from ( ( ( ( 1098.8 2732.3
activity concentration concentration
1 hour post 100 mg 100
169.1 386.5 hour post hour 953.1
4 [ [ its
Treatment Week Treatment Week 2303.2, 3241.3 ] [ 76.8, Treatment Week Treatment -
[ 1 [ P017 The geometric mean of the percent inhibition of of of percentinhibition the mean The geometric
. A202 by
.
Plasma Plasma
concentratio
with 47
5. studies including 2 phase II and 14 phase I clinical I and 14 phase II 2 phase including studies ]
dose . studies clinical I ase ] P013, - 79.7% ) ) ) ) ,
activity activity 200 mg 65 69 67 77
, 184.2] , 491.7] , 84.2 = = = = , 1171.6
4 , A202 in Study to 71.8 - n n n n 151.1 387.4 894.7 ( ( ( ( were Sitagliptin P012
foreign
61.1 , [ hours post hours 123.8 305.3
683.3 [ [ [ subjects/patients 1059 75.8 were of cases number the and 0.5 (
008 - subjects insubjects ph , analysis
. Plasma ]
5 ] ] ]
) ) ) )
Treatment Week 12 Week Treatment as shown in Table inTable as shown
65 77 66 64
, P001
adult dose , 37.4 , 57.4 , 94.1 , 153.7 , = = = = - at
a total of 16 of total a 33.0 51.0 81.9
Table Table n n n n 132.1 are ( ( ( ( Pre dose range of 25 range dose
29.0 45.3 71.2 in [ [ [ 113.5 P014 [
dose confidence interval confidence -
CI] A202
and had plasma concentrations plasma had and drug study received in who ts concentrations patien
. group twice daily mg 50 the in
] % ] ] ]
P010, confidence interval ) ) )
95% )
95
2
[ 66 70 69
77 32.9 60.4 ) pharmacodynamic
dose , , , 95.2 , 172.7 ] = = = 89.1 its
-
= consistent with with consistent is which concentration, Sitagliptin plasma on dependent was 4 activity
. administration twice daily 50 mg following 29.8 53.9 84.1 - n n n 148.8 nM n ( ( ( 95% Week ( ( Pre
plasma Sitagliptin concentration data obtained data concentration Sitagliptin plasma
26.9 48.2 74.3 in Study Treatment [ [ [ 128.3 [ with Sitagliptin Sitagliptin 86.4, its activity at pre [ the
Numbers Numbers in the 50 mg group and 77.3% [74.6, 79.7] in the in 79.7] [74.6, and 77.3% group mg thein50 4 100 mg 100 the in that to similar was A201 Study in activity 4
- -
dose was similar between Treatment Week 2 and Treatment Week 12 and increased with with increased and 12 Week Treatment and 2 Week Treatment between similar was dose ek 4 - dose in Study A201 were similar to those in Study in Study those to similar were A201 dose in Study
with Dose eometric mean sparse sampling data]) sampling sparse Using mellitus 2 diabetes type with patients clinical studies and I phase II phase analysis foreign Population of pharmacokinetic (b) Study According to
Sitagliptin Sitagliptin plasma of mean geometric the , A203 Study In 4 and 155.7 once daily administration mg 100 following respectively, respectively, pre the over dose increasing Plasma measured measured mg DPP plasma DPP plasma 70.1] who underwent a meal tolerance test at test tolerance a meal underwent who patients from DPP plasma inhibited completely almost relationship seen in healthy healthy in seen relationship DPP the geometric mean of the percent inhibition of DPP of inhibition percent of the mean the geometric 87.9% We 200 mg 200 25 mg 50 mg mg 100 G
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page48
, . .
, status
gender, dose of dose of
, 30 < In addition In healthy . obesity , renal were included in in included were dications
) 80 mL/min/1.73 80 mL/min/1.73 linear mixed effect effect linear mixed > . compartment model compartment - clinically meaningful meaningful clinically height , week washout interval week severe [ , and severe and foreign and foreign non- - ]
were screened for drug drug for screened were 2 ) , Study Number Number , Study 5.3.3.2.2 of Sitagliptin of ( using analysis are consistent with the the with consistent are analysis as [ normal
to have a to have receive a single 50 mg a single receive R
C concomitant me concomitant healthy subjects healthy varying degrees of , 6 formulations PPK , hemodialysis hour C with were to were identified pharmacokinetics 50 mL/min/1.73 m 50 mL/min/1.73 he basic model was a 2 a was model basic he
< renal insufficiency insufficiency renal , fedstatus . T
body weight body the requiring were were ) , ] , ] and of drug interaction studies interaction of drug and patients patients
with a Sitagliptin dose a Sitagliptin with
30 to 48 1.1
) at the results of the at the results ESRD
level . , creatinine
V and the background factors other than renal function were and the other than factors background renal function were 5 patients patients 5 diabetic status moderate [ , moderate t a 1 leas at by separated 2 doses receive
nducted to evaluate the pharmacokinetics, safety, and safety, to thenducted evaluate pharmacokinetics, ] ), 2 ≥ special populations serum serum CR , in version version patients with renal insufficiency renal with patients C [ (
24 Reference data , Reference (
] as covariates stage renal disease [ disease renal stage
. * 20** patients were to patients NONMEM 80 mL/min/1.73 m mL/min/1.73 80 and end- to ** ] examined 2
classified on the basis of24- basis on the classified insufficiency renal Pharmacokinetics in in Pharmacokinetics to < treated subjects ( oftware, clearance creatinine 3) s . 50 , (
label study in foreign adult male and female patientsfemale and male adult foreign in study label * 20** a population pharmacokinetic (PPK) analysis was performed performed was analysis (PPK) pharmacokinetic a population (2) ** degree of renal insufficiency renal of degree BMI [ mild [ mild , medications coadministered medications Foreign pharmacokinetic study in patients with patients in study pharmacokinetic Foreign , ]
2 ge 83 considered to have no clinically meaningful effect on effect meaningful clinically no tohave considered and dose were and dose . analyses and safety the pharmacokinetic Sitagliptin and ESRD and Sitagliptin adult male and female subjects was co was subjects female and male adult Sitagliptin of tolerability Patients with renal insufficiency excluding ESRD excluding insufficiency renal with Patients mL/min/1.73 m mL/min/1.73 Pharmacokinetic parameters are shown in Table 6. Table in shown are parameters Pharmacokinetic 30 the of All
P008 open- An race, 4.(ii).A. (a)
, studies insufficiency m medications these of none result, a As interactions. modeling A Based on the above, the applicant explained th explained applicant the above, the on Based effect on the pharmacokinetics of Sitagliptin of pharmacokinetics the on effect insufficiency renal with in patients a study of results
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page49
] ]
** ]
CI
and 58 for
0.027 0.001
NA NA ∞ 1.42 5.95 4.50 )
= <
) of fraction of 6 90% 0-
[ 151 P P 1.22, 1.65 5.04, 7.02 4.03, 5.03] , or = [ [ [ RD Mean ratio Mean
) n ( ES was
mean ∞ AUC was notwas increase increase 0-
foreigners
were also also were
(
0 continuous continuous increase in in increase t of plasma tplasma of ) max the 5.
NA NA 556 260 28.4 19.8 AUC squares squares fold increase was Mean increase was -
. There were no as a as fold and
- least
2.3-
fold
]
geometric in mean fold nterval CR ] ] ]
**
i - ] 1.6 ∞
headache
. 0.17 CI 0- the percen the
- 3.8- 4.5
0.696 0.001
While the t the While 0) 0.05
0.24
plicable; urine was not collected for ESRD ESRD for collected not was urine plicable; 1.75 5.22 0.18 3.77 rithmetic
) - = < Samplesize for .
a type 1 diabetes mellitus mellitus diabetes 1 type 6 90% <
. [ P P 1.51, 2.03 4.42, 6.16 0.16, 0.20 ; 0.30, 3.37, 4.22]
insufficiency = - [ [ [ [ onfidence onfidence AUC Mean ratio Mean
[ 1/2 c P n
t 037 ( ( =
: not ap P
One renal CI
CR
NA
creased
;
and model C model with , 3 events of 3 events of C , ∞ - , de 3.5 684 228 an approximately an 22.5 60.2 16.6 0.52 fold the e,0 life
Mean Severe - 033 , R P 2-
, an approximately an was prolonged with decreasing renal renal decreasing with prolonged was half
. subjects
] an approximately 029 ] ] ]
** 1/2 P ] , t , harmonic mean for
14
including laboratory abnormalities laboratory test including
of Sitagliptin by degree of renal insufficiency renal of degree by Sitagliptin of 0.05 CI ;
- ( ) ANCOVA s
0.771 0.001 ( 027
0.12 max 1.43 2.96 0.37 2.26 the ) P - t = < renal
6 , 90%
r , [ leading to discontinuation ) leading P P 1.23, 1.67 2.50, 3.50 0.33, 0.42 0.18, 2.02, 2.53] stomach upset stomach = - [ [ [ [ Mean ratio Mean
[ 017 n
( P
, . 49 arecorrelated with insufficiency
Moderate
glycemic symptom, which was classified as an as an classified was which symptom, glycemic hypo
013
P 24h
single oral dose ; median fo
a , 3.0 ∞ 560 129 126 R - increased and the Cl the and increased 19.1 0.64 9.96 C l Mean erminal phase elimination
t e,0 : 008 ∞ f 1 event of of 1 event P ) for historical) for controls. 0- 1/2 ,
t for for
,
50 mL/min was largely ≤ largely was mL/min 50 , and, , and C ] ] ]
following **
rithmetic meandifference reported for f 006 ] a P ≥ 24h
; dose 600 mg CI , max AUC )
- - C
0.011 0.303 , events adverse serious CR C
of covariance analysis 1.35 1.91 0.09 0.71 1.61 ) 003 = = ,
max 6 P 90% the
[ P ∞ P 1.15, 1.58 1.60, 2.28 0.63, 0.81 0.01, 0.16] 1.43, 1.81] , C = [ [ [ [ [ normal Mean ratio Mean
insufficiency 0- / ,
n ( ∞
hours post hours 0- P002
, , deaths renal subjects with normal renal function, renal withsubjects normal in patients with mild renal insufficiency renal mild with patients in
48
AUC
to P001 Four other events ( events other Four 3.0 242 527 16.1 Mild Mild 83.3 0.84 7.09 Mean clinical adverse events occurred in occurred events adverse clinical . rmacokinetic parameters
ha 26 (single oral doses of 1.5
)
* Hemodialysis removed Sitagliptin by only a modest extent and extent a modest only by Sitagliptin removed Hemodialysis renal insufficiency renal
(
including laboratory test abnormalities test laboratory including 82
in patients with moderate renal insufficiency renal moderate with inpatients 91 ompared ompared = 3.0
50 mg 3 339 43.7 13.1 0.76 4.40 Mean n was observed was ( Normal
squares mean for AUC - ∞
an approximately an and insufficiency, renal severe with patients in Sitagliptin p As c in ESRD patients requiring hemodialysis requiring patients in ESRD . 0-
.
6 .
, events ry adverse R
receiving insulin pump therapy had insulin pump receiving
l
) ) )
C ∞ ***
adjusted to ) 0- - ) nM h nM ) · Table ( h AUC (
at hemodialysis with Patients :
h
( and
(
h ∞ M
- R μ ∞ 24 max l AUC Dose - ( e,0 max 1/2
mL/min Parameter Geometric mean ratio Including the data from Studiesfrom data the Including ( events adverse was observed observed was . events transient moderate, or mild all were which reactions, drug adverse as classified laborato . As a result, the a result, As . variable geometric mean in subjects with C with subjects in mean geometric observed
, renal function decreasing With C t t f C ( C
altered markedly in patients with renal insufficiency renal with inpatients markedly altered . subjects healthy protein binding in patients with renal insufficiency was similar to that in healthy subjects in healthy that to similar was insufficiency renal with in patients binding protein safety, Regarding patient adverse drug reaction drug adverse the function Analysis was performed using an using performed was Analysis observed e,0
* ** *** Geometric least ESRD f patients hemodialysis on dose excreted unchanged in urine extrapolated to infinity to extrapolated urine in unchanged excreted dose
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page50
a (
and were
s was
] ] ] ] )
*
1
CI]
There were ) squares mean of 0.726 0.69 . -
0.05, 0.07 0.05, 0.68, 1.02 0.68, 0.91, 1.42 0.91, 1.01, 1.46 1.01, ), subjects = = - [ [ [
[
[90% P P 8 Mean ratio Mean , Study , Study 5.3.3.2.5 ifference of arithmetic ( 0.83 1.13 1.21 d 0.01
obese adult males obese adult ), /
years, ) (foreigners healthy subjects healthy arithmetic least arithmetic including laboratory test test laboratory including
( ; 45 [control] - 10 1/2
t . discontinuation to leading
, control 18 ) ) (
was conducted to evaluate the the evaluate to conducted was
.
-∞ control ) . ( adult females adult ) e,0
/
f
10 occurred in 1 patient with hepatic withpatient hepatic in 1 occurred
=
for for
1.5 healthy subjects healthy 292 13.9 9.49 ) subjects ) 1046 / n 0.681 (
squares mean for - 10 , 2 s [control] Healthy subjects Healthy headache
events adverse serious classified as adverse drug reactions drug adverse as classified
-∞ ,
e,0
Reference data , Reference ) all 50 ] 40 kg/m40 mild mild administered. administered. - ; harmonic least ; harmonic
deaths max were healthy subject healthy
and foreign healthy adult male and female subject female and male adult healthy foreign and * 20** s of
healthy adult female subjects ( subjects female adult healthy )
) , BMI30
)
controlled study in foreign healthy elderly male and female female and male elderly healthy in foreign study controlled
10
= elderly males and females and males elderly
dose pharmacokinetic parameters of Sitagliptin parameters of dose pharmacokinetic 1.8 243 14.4 , which 1186 - n 11.51 * to ** 0.689 ( patients ; median for t
including laboratory test abnormalities test laboratory including R s scale 10 patients with hepatic insufficiency hepatic with 10 patients , years ** ’ Reference data , Reference ( moderate hepatic insufficiency patients insufficiency hepatic moderate Cl [ ( adult male and female patients with moderate hepatic insufficiency hepatic moderate with patients female and male adult
45 . Single 7 Pugh , and 20**] - urine extrapolated to infinity for f for infinity to extrapolated urine 18- P003 Moderate hepatic insufficiency ( subjects each * max
C of Sitagliptin was to be was Sitagliptin of blind, placebo- blind, of Sitagliptin were higher in patients with moderate hepatic insufficiency than than insufficiency hepatic moderate in with patients higher of were Sitagliptin - , 10 Table Table
Child ∞ 0-∞ to**
healthy subjects healthy squares means 0- , events adverse laboratory clinical adverse event adverse clinical
- . , subjects s , years *** subjects treated
[ r . analyses safety and pharmacokinetic AUC moderatehepatic insufficiency patients - , or adverse events ( events adverse , or )
80 safety, safety, ) 9 the on
- h in patients with moderate hepatic insufficiency and healthy subjects healthy and hepatic insufficiency patients moderate with in
and ･ ) 65- label study in foreign in label study P017
(
Paramete M μ ) ( max
∞ ) C - nM Foreign pharmacokinetic study in patients with hepatic insufficiency hepatic with patients in study pharmacokinetic Foreign ) 0 Foreign single Foreign study dose in ( h mL/min
squares mean AUC for h ( ( hypoglycaemia
- squares means ( ( ∞
- - R max l , Study Number Number , Study 5.3.3.3.1 e,0 max 1/2 Ratio ofgeometric least AUC C t t f C in healthy subjects, but without significant difference, which were not considered to be clinically clinically be to considered not were which difference, significant without but subjects, inhealthy effect meaningful included in the male adult obese subjects ( double randomized, A (c)
The score of 7 of score of Sitagliptin and safety pharmacokinetics the to evaluate conducted 100 mg of dose single A 7. Table in shown are parameters Pharmacokinetic 20 the of All An open- An (b) Number safety, tolerability, and pharmacokinetics of a single dose of Sitagliptin dose single of a pharmacokinetics and tolerability, safety, Regarding no abnormalities insufficiency and 3 and insufficiency
fraction of dose excreted unchanged in in unchanged excreted dose of fraction Least * least
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page51
,
< day just with for 4
) female female ) diabetes % and including including
( 6.5
**] adult and and a 7- and ≥ /
to be orally ) , 1C respectively, and and respectively, was was , activity over time time over activity ]
elderly with corresponding corresponding with ( ” group to *** 20 4 )
- * 2 events of somnolence 2 events ** , male alone [ 0.2 mg ratios
months, with HbA with months, , respectively ,
3 administration of Sitagliptin Sitagliptin of administration 1.04, 1.46 - . events adverse or , max ) patients with type 2 type with patients
C following the administration of of the administration following / female ( . 1.23 [
There were no laboratory adverse adverse laboratory no were There s . voglibose and voglibose ly administered three times daily daily times three administered ly orally administered once daily in the the in daily once administered orally “
] 1.23, 1.73
( and and [
∞
ratio multiple co multiple or 0-
subjects within the previous previous the within ),
max to be 8
1.46 C after after AUC . to be oral was
and and ” group
, 1.43] 1.19
The
healthy elderly males and females, healthy adult adult healthy females, and males elderly healthy ∞ ] was was 51
0-
days 4 for meal abdominal discomfort abdominal of vent . peptide > 0.7 ng/mL ng/mL 0.7 > peptide the - 100 mg 100 , Study Number P046 Number , Study 5.3.3.4.1
1 e AUC (
( . values voglibose on the the on of voglibose effect the to evaluate conducted was 0.2 mg 0.2 each each the percent inhibition of plasma DPP plasma of inhibition percent the
the 0.97, 1.17
. Thus, one of the factors contributing to higher plasma to higher plasma contributing offactors theThus, one . [ across [ 1.31 s were max ]
C that that administration
- before before
0.77 Sitagliptin co
“
including laboratory test abnormalities test laboratory including ), ( ( inJapanese study crossover period, similar just . leading to discontinuation leading ) 0.63, [ s were 1.07 s were ” group orally administered once daily in the morning in the in the fasted state daily morning to once administered be orally
e was e was were classified as adverse drug reactions drug as adverse classified were subjects in6 events to be administered be to placebo was or Sitagliptin 270 mg/dL, and fasting serumC subjects were included in the pharmacokinetic, pharmacodynamic, and safety safety and pharmacodynamic, pharmacokinetic, the in included were subjects
label, 3- included between periods included ≤ clinical adverse events occurred in occurred events adverse clinical
was was confidence interval confidence 8 alone ,
90% treated treated .
meal for 4 days for days 4 meal of which 6 of which arget number of cases of 12) cases of of number arget Drug interaction studies interaction 4) Drug 38 100 mg . t
,
( 0.69 was ratio
in .
2 (2) events adverse serious each each Sitagliptin Sitagliptin R “ l confidence interval confidence ( C
- , open randomized
Patients on diet and exercise therapy who hadnot received an antidiabetic agent aboratory test abnormalities aboratory
washout interval was was interval washout morning in the fasted state and voglibose state infasted the morning before before daily times three administered the days days of Sitagliptin and pharmacodynamics pharmacokinetics showed analysis Pharmacodynamic dos single a following concentrations in the elderly was considered to be reduced renal function renal reduced be to considered was elderly the in concentrations 90% corresponding corresponding and voglibose Sitaglipt 2 Sitagliptin mellitus 4.(ii).A. with(a) interaction Drug study voglibose A
males adult obese and females, safety Regarding ) 3 events of headache l , analysis to pharmacokinetic According All of the the All of analyses 50 mg of dose single A 10.0%, fastingblood glucose subjects exhibited modestly higher modestly exhibited subjects , events
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page52
s 12 to on 0-
90% ) AUC adverse adverse all of the the of all
(2 ), but a), but feeling feeling confidence confidence (
), but a
concomitant concomitant and
nt) and placebo serious geometric mean mean geometric , . ,
administration, the the administration, confidence interval confidence max
increased pharyngitis days
Reference data Reference enrolled
C 4 activity over time over 4 activity , , - geometric mean ratios mean geometric . ]
CK
with corresponding corresponding with and metformin
max ) 12 to C
0- d the plasma Sitagliptin plasma the d *** 20** ing coadministration compared to to compared coadministration ing and including laboratory test laboratory including herpes zoster AUC (
administration and there was a trend a trend was there and administration
* to There were no deaths were There - placebo 24 Sitagliptin .
/ 0- Two laboratory adverse events were were events adverse laboratory Two ** + . .
[ administration group (1 eve (1 group administration drug interactions following interactions drug - 2 events) patient was additionally was patient
was shortened by 1 hour by shortened was respectively, an respectively, 50 mg
group alone Sitagliptin the of subjects 2 , in foreign patients with in foreign with patients period, study crossover )
increased andAST blood increased
( 52 metformin , respectively, co - and following , respectively, investigate ] 1.05 ] , or adverse events ( events adverse , or , and ) 2 hours on Treatment Day 7 with corresponding 90% corresponding 7 with Day Treatment on ( the plasma AUC plasma the
0.77 Sitagliptin Sitagliptin alone group (
)
0.89 the plasma metformin plasma the
, [ max t one group one group controlled, 3- 1 subject of the co the of ), 1 subject al metformin + Sitagliptin + metformin 0.56, ( 0.97 on Treatment Day 3 with corresponding 90% corresponding with 3 Day Treatment on [ )
orally administered twice daily for 7 for daily twice administered to were be orally of Sitagliptin Sitagliptin of 1000 mg
and metformin
/
0.66 alone . , Study Number P012 Number , Study 5.3.3.2.4 ( doses ] 1.09
and and
alone blind, placebo- blind, 1000 mg 1000
- litus was conducted to metformin 0.95,
[ min Sitagliptin ] 0.89 + /
multiple clinical adverse events occurred in occurred events adverse , clinical the percent inhibition of plasma DPP of plasma , the inhibition percent analysis harmacodynamic treated subjects were included in the pharmacokinetic, pharmacodynamic, and safety safety and pharmacodynamic, pharmacokinetic, the in included were subjects treated
. to discontinuation ) leading 0.77, metfor [ , analysis topharmacokinetic voglibose the of subjects and 2 geometric mean ratios mean geometric 12 50 mg
+
), g to p pain in extremity in , pain constipation . diabetes mel diabetes ( including laboratory test abnormalities test laboratory including 1.02 were s metformin + Sitagliptin + metformin max ( 0.83 2
rding C administration -
bnormalities co Sitagliptin one more in 1 patient, compliance placebo toDue poor . analyses safety and the pharmacokinetic in included were subjects 13 treated interval exposure was decreased and the median median the and decreased was exposure ratios and were were ( Acco (b) interaction Drug study double randomized, A
analyses safety Regarding
, analysis topharmacokinetic According the All of events) events) Accordin type administration ofadministration Sitagliptin abnormal Treatment Day 3 was similar between Sitagliptin alone and co and alone Sitagliptin between similar was 3 Day Treatment follow test tolerance ina meal levels glucose blood lower towards voglibose or Sitagliptin reported by 1 subject of the voglibose the of 1 subject by reported causal relationship to the study drug was denied for all events all for denied was drug theto study relationship causal causal relationship to the study drug was denied for both events both for denied was drug theto study relationship causal ( events a
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page53
, , ] ]
. 1.09 light
20** 20** dose of dose of dose of dose of , 1 mild , 1 mild
* s
following following ( *** ** mg
oratory test s were concomitant concomitant mg
to to serious adverse adverse serious There were no 1.25- ,
*** subject but all events were were events all but *** [ [
,
subjects excluding 1 excluding subjects
of Sitagliptin on the the on Sitagliptin of of Sitagliptin on the the on Sitagliptin of geometric mean ratios mean geometric following 8 deaths
including lab including P031 ( P025 including laboratory test max ch ( . discontinuation to leading C respectively, indicating that that indicating respectively, ) , confidence interval confidence ] astrointestinal disorder astrointestinal
and g of whi
( ∞ Number Number all occurred occurred all 1.15
0-
( 90% and in 1 event 1
.
) ; infection tract respiratory upper AUC , 0.95 subjects
[ dose administration dose administration 2 and - -
1.05 in foreign healthy adult male and female subjects subjects female and male adult healthy foreign in events adverse serious
inseverity , or adverse events events or adverse ,
, , events adverse laboratory , Study Number Number , Study 5.3.3.4.7 ) 53
( , Study 5.3.3.4.5
( multiple anxiety and
ia, .
glibenclamide with corresponding corresponding with once daily on Days 1 to 6 with a single a 6 with 1 to on Days once daily deaths
pharmacokinetically )
] 1.08 was mild was the was classified as an adverse drug reaction drug adverse as an classified was ,
respectively, indicating that Sitagliptin does not affect the the affect not does Sitagliptin that indicating respectively, were classified as adverse drug reactions. reactions. drug as adverse classified were , )
200 mg 200
0.97, . [ glibenclamide including laboratory test abnormalities test laboratory including ofwhich 3 events in 1 subject the effect of multiple the effect the effect of the effect ( anxiety metformin 1.23] alone ),
glibenclamide period, crossover study in foreign healthy adult male and female subjects subjects female and male adult healthy foreign in study crossover period, period, study crossover the /
2-
nclamide
, 0.84 [ events 3 these of clinical adverse events ( events adverse clinical clinical adverse events occurred in occurred events adverse clinical label, 2- label, 1 s were 1.02 3 metformin 1.01 administered with Sitagliptin on Day 5 or receive a single 1.25- a single or receive 5 Day on Sitagliptin with administered 11
There were no hypoglycaem were There - , receive Sitagliptin receive , , events adverse laboratory . ) ) , , or adverse events adverse , or moderate events moderate and . to discontinuation ) leading ) , analysis safety the in included were subjects treated
were noted and due to consent withdrawal were included in the pharmacokinetic analysis pharmacokinetic the in included were withdrawal consent to due discontinued
9 10 were to were including laboratory test abnormalities test laboratory including ( ] 1.24 dose pharmacokinetics of glibenclamide dose pharmacokinetics -
0.96, glibenclamide + Sitagliptin + glibenclamide single investigate to conducted was events abnormalities pharmacokinetics of glibepharmacokinetics safety Regarding [ severity in mild A randomized, open - randomized, A (d) Drug interaction study with simvastatin investigate conducted to was According to pharmacokinetic analysis topharmacokinetic According the of All Subjects (c) Drug interaction study with open- randomized, A
safety Regarding interval confidence ( ) headedness subject who subject glibenclamide co glibenclamide Sitagliptin does not interact with interact not does Sitagliptin Reference data Reference glibenclamide on Day 1. on Day glibenclamide data Reference event and and event of administration hypoglycaemia administration and administration abnormalities
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page54
, , + ]
for the **] 0.98 0.94
, , 0.59 1.32 [ 20 200 mg 200 and
aboratory aboratory 0.88 *** . , 0.86 5 events of of events 5
[ s were ( simvastatin to
( ] 1.26
two l were classified and and
-
) 1.06 *** , respectively , Sitagliptin Sitagliptin [ once daily on Days ]
on Day 5. on Day 0.88,
months and required and required months ] 1.28 [
and of Sitagliptin on the the on Sitagliptin of geometric mean ratios mean geometric
Twent y 1.26 ]
. P034 4 mg
, 0.80 max [ 200 mg 1.35
C , 0.51 [ confidence interval 1.01 and
for about 2 , occurrences 3 least at with events s were 1.06 s were , 0.93 ( subjects 4 in events
[ d ∞ 0.80 1 event of vomiting 0- geometric mean ratios mean geometric leading to discontinuation ) leading administration
on Day 5. on Day
in the fasted state or
and max associated with associated those were events AUC
subjects
C dose - 10 4 mg foreign healthy adult male and female subjects subjects female and male adult healthy foreign of which 8 20 mg
1.22] hich persiste and or Sitagliptin Sitagliptin or 20 mg
),
last 54 , Study Number Number , Study 5.3.3.4.8 confidence interval confidence 0- (
multiple
0.60,
. of which 21 of which . simvastatin AUC with corresponding 90% . analyses safety and pharmacokinetic the in CoA reductase inhibitors, CoA unlikely related to the study drug study the to related unlikely - the ) , the . analyses safety and pharmacokinetic the in ded respectively, indicating that Sitagliptin does not affect the the affect not does Sitagliptin that indicating respectively, and resolved. As a serious clinical clinical a serious As resolved. and severity or in moderate mild
in 1 subject, w insubject, 1 , all reductase 1.12 inhibitors, CoA judged judged that rosiglitazone - , heaviness stomach of 1 event , subjects , the effect of the effect rosiglitazone simvastatin
1.12] 2 were were and no serious laboratory adverse events were reported. There were no no were There reported. were events adverse laboratory serious no and
in study period, crossover
rosiglitazone / developed showed but
for active HMG active for including laboratory test abnormalities test laboratory including , 0.88 , , [ and 3 events of throat sore and with corresponding 90% corresponding with ) ysis ysis clinical adverse events occurred in in occurred events adverse clinical label, 2- the event was was the event al for total HMG
0.99 , pneumonia 29
receive a single dose rosiglitazone of dose a single receive
receive a single dose of simvastatin dose a single receive ) pneumonia and and 0.85 acid, simvastatin for treated subjects were included were subjects treated treated subjects were inclu were subjects treated
respectively
, , to pharmacokinetic analysis to pharmacokinetic . pharmacokinetics of pharmacokinetics simvastatin 1 event of gastric pain gastric of event 1
/
administered with a single dose of dose a single with administered , were to were were to ] 1.02 dose pharmacokinetics of pharmacokinetics dose dose mentioned mentioned respectively 1.34] - - - ,
rosiglitazone + + Sitagliptin rosiglitazone 0.93, 0.66, Reference data Reference ( According single Subjects with study interaction (e) Drug open - randomized, A investigate conducted to was with a single dose of rosiglitazone dose of single a with 1 to 5 coadministered on Days once daily Subjects Subjects 12 the of All single 1 to 5 co- 1 to 5 12 the of All [ an Pharmacokinetic Sitagliptin [ simvastatin hospitalization, but hospitalization, in occurred events adverse 10 events of headache Regarding safety, Regarding above headache event, adverse respectively ( events adverse or deaths as adverse drug reactions drug as adverse 1.31]
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page55
,
, , , ] 1 2 ] of , , ), tsof ] 1.21 1.36
20** 1 event
nausea even Sitagliptin 1.12, 1.01, leading to *** [ 4
of dizziness ) , to , nausea 1.24 [ , 1 subject due to to due subject 1 , doses doses *** including laboratory laboratory including given concomitantly concomitantly given [ and and 2 events of 2 events events with at least 3 3 least at with events
ratios mean geometric ( , dizziness mg
5 events of headache 5 events - s were 1.11s were
( to be to be 5 events of events 5 1 eventof excluding 3 subjects who max
] 1.29 P018 , 100 were included in the safety inthe safety included were C ) ere ) withdrawal w subjects clinical adverse events occurred occurred events adverse clinical , 1.08
and [
events with at least 3 occurrences 3 least at with events
( 24 24
. subjects 0- dizziness, 4 events ofevents 4 subjects 1.18 , 20 21 were classified as adverse drug reactions drug adverse as classified were , concomitant concomitant following interactions drug AUC and
, ) , subjects serious adverse events ( events adverse serious 6 events of headache confidence interval confidence .
(
, 7 In Part II, subjects in5 events
due to consent dueto consent
.
Part II dyspnoea digoxin digoxin of doses 3 events of of events 3
period, crossover study in foreign healthy adult adult healthy in foreign study period, crossover Part II 90% ,
lethargy deaths 55 mg alone - . altered not was of digoxin investigate given concomitantly with with concomitantly given
R
, Study Number Number , Study 5.3.3.4.3 ( and digoxin and including laboratory test abnormalities test laboratory including in severity except for 1 severe adverse drug reaction of of reaction drug adverse severe 1 for except severity in 0.25
moving out of the area area the out of moving to due study of clinical the II Part subjects; once daily for 10 days
headache subjects; of which 10 of which events of events event of of event to be digoxin
12 ), 1 5 were classified as adverse drug reactions, but were all mild in in mild all were but reactions, drug as adverse classified were 15 , controlled, 2- , ere ) , Part II, digoxin subjects 4 in events w
with Sitagliptin mg 100 , . 10 Part I of Sitagliptin ( Part I with corresponding corresponding with
( 9 events of events 9 discontinued ( warmth )
ch dizziness , headache doses who
- placebo blind, of whi subjects - digoxin
/ clinical adverse events occurred in occurred events adverse clinical , respectively rosiglitazone ] 32 , or adverse events ( events adverse , or 1 ofevent digoxin digoxin of doses
19 2 events of 2 events ,
multiple
g , , 9 events of headache , 9 occurrences 3 at least with events ) 1.33 ( events of dysmenorrhoea of events m ith Sitagliptin 200 mg, but the Cl 200 mg, ith Sitagliptin subjects treated
- Part I of the clinical study (2 subjects (2 study clinical the of I Part 3 ), headache , w , , 1.05 subjects in8 events noted in 1 subject treated with treated in subject 1 with noted fatigue 0.25 of which Sitagliptin or placebo placebo or mgof doses Sitagliptin
[ , events adverse laboratory no were There -
, . 15
200 1.18 Part I
digoxin + + Sitagliptin digoxin 6 events of 6 events Reference data Reference event ofevent vomiting ) abnormalities test , 15 events of of events 15 , occurrences ( administration of administration male and female subjects was conducted to to conducted was subjects female and male digoxin plasma the that showed analysis Pharmacokinetic All of the 36 the All of In A randomized, double randomized, A with study interaction Drug (f) Regarding safety, safety, Regarding of pharmacokinetics severity discontinuation. Regarding safety, in Part I, 44 clinical adverse events occurred in 8 occurred events adverse 44 clinical I, Part in safety, Regarding moderate or mild and transient all but were headache respectively events of of events subjects in 11 pregnancy) and 1 subject discontinued In days. for 10 daily once or placebo palpitations and with with analysis, which . analysis inthe pharmacokinetic included were
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page56
, , ,
) ] 1 1 , ). **] 1.02 20 pruritus 0.90, *** [ respectively. respectively. , to There were no
daily dosing with with daily dosing discontinued from from discontinued - ). 0.93] *** [ Based on the above the on Based , but were all transient transient all were but
. of Sitagliptin on the the on Sitagliptin of 2 events of events , 2 geometric mean ratios mean geometric who who . serious adverse events adverse serious s were 0.95 s were
with corresponding 95% corresponding with 0.86 , ) [ P022 geometric mean ratios with with ratios mean geometric max
C pharmacodynamic, and safety safety and pharmacodynamic, max 0.89 , deaths headache : International Normalized Ratio Normalized : International and respectively events with at least 3 occurrences 3 least at with events warfarin
( / ,
and ∞
and C effect on the pharmacokinetics or or pharmacokinetics the on effect 0- INR ] ∞ (
0- except 1 subject subject 1 except ) abnormalities test laboratory including ] 1.17 ( including laboratory test abnormalities test laboratory including 1.03 motor vehicle accident vehicle motor AUC ( confidence interval confidence
dose administration 10 events10 of - AUC ( , 1.00 , of fingers of, 1 event paraesthesia n left hand [ 0.95,
was towas be given on Day 1 [
11 days 11 5 during ofDay on once 56 warfarin 1.08 , events adverse ry
0.99 ) , Study Number Number , Study 5.3.3.4.4 warfarin - ( 30 mg 7 subjects
warfarin + + Sitagliptin warfarin and ( S(
]
R(+) the prothrombin time the prothrombin
. events adverse or , ) 1.06 , reactions drug as adverse classified were
were classified as adverse drug reactions, but were all mild or or mild all were but reactions, drug adverse as classified were
) events in events ) discontinuation treatment serious adverse event adverse serious with corresponding 90% corresponding with 0.96, the effect of multiple of effect the
no [ ) . as nausea period, crossover study in foreign healthy adult male and female subjects subjects female and male adult healthy foreign in study crossover period, vomiting
cs of warfarin 1.01 ( events adverse serious or deaths, was to be given given tobe was 30 mg
of which 17 There were no laborato warfarin / geometric mean ratios mean geometric . Therew
clinical adverse events occurred in 8 subjects in8 occurred events adverse clinical label, 2- confidence intervals were were intervals confidence respectively, andthe , respectively,
. ] s were of warfarin max or a single dose of warfarin of dose or a single s 25
1 event of
1 event of , ) , 0.92 cokinetic pharma the in included were subjects treated INR
12 200 mg 200
0.86, and fatigue
[ g safety, g . dose pharmacokineti 168 - 0- clinical study due to a non- a to due study clinical photophobia
warfarin + Sitagliptin + warfarin including laboratory test abnormalities test laboratory including numbness in ofevent numbness i right hand of, 1 event numbness ofevent severity in moderate ), headache of 10 events the , events adverse laboratory Regardin pharmacodynamic to have no clinically relevant clinically no have to considered was Sitagliptin confidence interval confidence single AUC corresponding 90% corresponding A single dose of warfarindose single A A randomized, open- randomized, A (g) Drug interaction study with warfarin of investigate conducted to was ( and 0.89 Pharmacodynamic analysis indicated that indicated analysis Pharmacodynamic and mild in severity and mild Sitagliptin the All of Reference data Reference analyses ( . to discontinuation leading Pharmacokinetic analysis showed that thethat showed analysis Pharmacokinetic
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page57
, , ) * ] but 28) and ** 600 oral
,
days dose ( -
ences, ences, ] 1.07 20** to alities
geometric geometric ***
*** 3 events of of events 3 0.89, s were 0.99 s were [ occurr [
, max to
* cyclosporine 0.98 of Sitagliptin and and Sitagliptin of
** [ and C
on the single the on
and and
once daily for 21 serious adverse events adverse serious
] 24 , 0- 1.09 geometric mean ratios mean geometric
AUC
deaths placebo confidence interval
4 events of nausea of events 4 max administration administration , , 0.97
C - events with at least 3 least at with events [ ( cyclosporine ). co 90%
]
and .
P026 Number .4.6, Study with a single dose of including laboratory test abnorm 24 matching ( NET 0- [ placebo on Days 22- placebo on Days oral contraceptive 5.3.3 (
28, AUC 2 1-
corresponding
57 , Study Number P037 Number , Study 5.3.3.4.9 ( 4 events of dizziness4 events Days Days ( with
norethisterone / s to be administered
] 2 dverse events were classified as adverse drug reactions drug adverse as classified were events dverse . days wa events adverse or , ) EE Sitagliptin or or doses of Sitagliptin the plasma EE the plasma [
period, crossover study in foreign healthy adult female subjects subjects adult female foreign healthy period, in study crossover oral contraceptive oral was to be coadministered coadministered be to was respectively, and the plasma NET plasma the and respectively,
mg , - cyclosporine ] an 100 mg
90% confidence intervals were 1.03 were intervals confidence 90%
200 period, crossover study in foreign healthy adult male subjects was subjects was male adult healthy in foreign period, study crossover - in Sitaglipt of coadministration multiple following interactions drug 1.10 the effect of a single dose of dose single a of effect the ,
) contraceptive oral
/
events in 11 subjects were observed with with observed were subjects 11 in events controlled, 2- , of drowsiness 8 events 0.86 [ All of the clinical a clinical the of All ) , ethinyl estradiol ethinyl label, 2 label,
. subjects 14 in occurred events adverse clinical the oral contraceptive ( investigate investigate 38
0.97
corresponding investigate )
. analyses safety and pharmacokinetic the in included were subjects treated and o
. analyses safety and the pharmacokinetic in included were subjects treated , indicating that the concomitant administration of Sitagliptin does not affect the the affect not does Sitagliptin of administration concomitant the that indicating , of which 21 ] ), 21). 1.06 Reference data , Reference
coadministered with with to be coadministered oral contraceptive a single dose of Sitagliptin Sitagliptin of dose or single a
0.93, Days 1- Days including laboratory test abnormalities test laboratory including [ 10 events of headache Regarding safety, Regarding respectively of pharmacokinetics an oral contraceptive was conducted to was conducted for 28 daily once The contraceptive oral ( 18 the of All contraceptive + Sitagliptin + contraceptive mean ratios with with ratios mean diarrhoea the ( . to discontinuation leading , events adverse laboratory no were There transient. and all were mild
All of the 8 the of All 100 mg Sitagliptin of dose single A A randomized, open - randomized, A t conducted with study interaction (i) Drug that showed analysis Pharmacokinetic . of Sitagliptin pharmacokinetics A randomized, placebo- randomized, A (h) Drug interaction withstudy 20**] was was mg Reference data Reference
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page58
, 80 for
. As 1.24 ≤ [ trough analysis
and then Based on involving and the . , or adverse ) PPK 50 and plasma trough trough plasma 203) , both of which of which , both
) ) >
was evaluated was 1.29 s were
. CR - A201 203), C considers as follows, as follows, considers ( - patients with mild or or mild with patients
/
geometric mean ratios mean geometric vomiting
P008 Study In There were no laboratory laboratory no were There .
50 mL/min A201 max
. ( and ≤
C in patients with mild renal renal mild with patients in fold in patients with moderate moderate with infold patients ients of Sitagliptin of
appropriate dosea to establish
∞ moderate renal insufficiency are are insufficiency renal moderate and 0-
pat and mild renal insufficiency renal mild 2.3-
nausea 30 confidence interval confidence patients ( ∞ overseas.
0- for recommending dose adjustment for recommending >
AUC pharmacokinetic variability, focusing on on focusing variability, pharmacokinetic and transient and
analysis, and a clinical study in diabetic study and a clinical analysis, CR foreign 90%
C AUC ( increased increased patients with moderate renal insufficiency, and and insufficiency, renal moderate with patients
diabetic the , be it should PPK
∞ 8 0- ,
the Japanese data on data Japanese 58 from sponding sponding including laboratory test abnormalities test laboratory including , ( AUC . to discontinuation ) leading fold in patients with Therefore .
factors leading to leading factors
reported reported 1.09- basis as the used were it was decided to recommend no dose adjustment for patients patients for adjustment no dose recommend to decided was it . with corre atients with mild renal insufficiency ( insufficiency renal mild with patients DA ) that the Sitagliptin the Sitagliptin that
45 in patients with renal insufficiency, PMDA renal insufficiency, with patients in
and though the though and ) P028 to those , P008 Study In investigate investigate by PM , analysis the effect of renal function on the AUC on the function renal of the effect
increased increased were compared by dosage and dose regimen. As a result, the trough trough the a result, As regimen. dose and dosage by compared were for Japanese patients with renal insufficiency, referring to the dose to the referring dose insufficiency, renal Japanese with patients for
.
in patients with moderate or severe renal insufficiency renal or severe moderate with in patients fold. renal function higher than normal that in with subjects for patients with renal insufficiency renal with for patients - Sitagliptin was performed using the data from phase I and phase II clinical studies studies clinical II phase and I phase the data from using performed was / , respectively , and ] PPK , the results of this study of this results the AUC similar ies
ts with mild renal insufficiency renal mild with ts of Sitagliptin of clinical adverse events occurred in 1 subject 1 in occurred events adverse clinical Japanese and foreign subjects with normal renal function renal normal with subjects and foreign Japanese 2
, 2.08 1.36 in patien [ of Sitagliptin
Sitagliptin Sitagliptin the use data and the recommendation
176
and 1 patient with moderate renal insufficiency insufficiency renal moderate with patient and1 the
Use in patients with renal insufficiency renal with patients in 1) Use the value was the value asked the applicant to the applicant asked Outline of the review ( including laboratory test abnormalities test laboratory including phase II clinical studies in Japanese type 2 2 type Japanese in studies clinical II phase
P008 rate renal insufficiency rate renal and 1.68 and ents with moderate renal insufficiency renal moderate with ents the
plain the use Sitagliptin + cyclosporine+ Sitagliptin with mild renal insufficiency renal mild with Study Study a result, a result, adjustment concentrations were measured in in measured were concentrations diabetes mellitus patients mellitus diabetes adjustment recommendation adjustment pati Concerning The applicant responded as follows: as responded The applicant 4.(ii).B. clinical studies phase II Japanese from patients Japanese inrenal function, In 4.(ii).B PMDA showed analysis Pharmacokinetic events adverse serious deaths, events, adverse ( events ( mild were but reactions, drug adverse as classified were 1.34] safety, Regarding of foreign clinicalof stud foreign containing containing insufficiency was about was 1.6 insufficiency patients with renal insufficiency ( insufficiency renal with patients renal insufficiency and insufficiency renal ex mL/min) comparable were concentrations limited, limited, concentrations mode foreign patients with renal insufficiency, the Sitagliptin Sitagliptin the insufficiency, renal with patients foreign
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page59
. , of the he
for the the the the
, and
”
P028 , PMDA 50 mg (b) , ication No. No. ication based on the based the on , guide for
outside outside altering Notif
modeling , Although t Although s increase in increase . 0.66, the blood fell inJapan ug interaction ug and
, and, Study
dr 813 dated June 4, 2001]) 2001]) 4, June dated 813
fold . Meanwhile, in some drug drug some in Meanwhile, . was the Japanese clinical clinical the Japanese
2 ing P008 P008 as a [PFSB/ELD -
” to digoxin digoxin studies eatment with Sitagliptin with eatment - 1.68
is different between Japan Japan between different is evaluat carbohydrate tudy tudy
S In
. . ] Methods of Drug Interaction Studies Interaction Drug of Methods ” concomitant medications when when medications concomitant term tr term “ cyclosporine -
/Sitagliptin) icacy and information safety from the relevant a caution statement in the package inthepackage statement caution a that are considered correlated with with correlated are considered that oreign oreign that the amount absorbed following absorbed thatthe amount administered to patients with severe severe with patients to administered o safety data from Japanese patients patients Japanese from data safety o
resulted in a SB/ELD Notification No. Notification SB/ELD , and corresponding corresponding ; the proposed dosage ; proposed the is F P ) , etc. , covariates as etc.) [
, ” with normal renal function renal normal with the exposure will be similar to that at the the at that to similar be will exposure the
the dosage usual , , a number of including including andabsorption of
25 mg indicating , digoxin ( There are n , of
specified range for Sitagliptin pharmacokinetic studies or studies pharmacokinetic Sitagliptin for range specified , e.g. factors , e.g. - specified by the applicant the by specified . once daily 24
AUC
0- patients
analysis of foreign clinical clinical foreign of analysis
59 n digestion compared to Sitagliptin alone to Sitagliptin compared greater was be taking Interaction Studies Interaction
AUC (Sitagliptin + voglibose + (Sitagliptin voglibose PPK 100 mg 100
the
also t from the pre the
many factors many in the tration with cyclosporine with tration Guideline for Bioequivalence Testing of Generic Drugs “ bodyweight and BMI
es Patients with renal insufficiency renal with ) Patients , may
.1 , overseas , P008 CR affected
pplicant to explain the necessity of dose adjustment dose of necessity the explain to applicant the asked Methods of Drug of Methods 4)
“ ( e acceptanceranges as specified inthe notification
who who includ of Sitagliptin of
changes
and there is a safety concern about long about concern safety a is there and .B. is coadmin
coadministration coadministration andC ) )
iii PMDA ( ratio ] and the the ]and
4. over a long period of time at exposures at exposures ofperiod time a long over
the use of Sitagliptin in patients with moderate or severe renal insufficiency renal severe or moderate with inpatients of Sitagliptin use the max the gastrointestinal tract, which may have affected the absorption of Sitagliptin. Sitagliptin. of absorption the affected have may which tract, gastrointestinal the presented presented model needs more consideration more needs model , and (c)
ee “ s in . Thus, nalyses, and clinical efficacy/safety profile of Sitagliptinthe andapplicant had specified the range for Sitagliptin creatinine [ dose recommended by the applicant by recommended dose
inhibitory action action inhibitory a
e results of Study Study of results e 100 mg/day PPK determining whether dose adjustment is required for patients with renal insufficiency with for patients is required whether adjustment dose determining the model model the approved dosage the approved ( f Sitagliptin for serum
at present, present, at Drug interaction studies with with studies interaction 1) Drug . I when coadministered with these drugs and drugs these with coadministered when the effect of renal the on effect function Sitagliptin the mean C mean the
)
). ,
data based theon bioequivalenc PPK Drug interactions interactions 2) Drug lowering effect of effect lowering Sitagliptin ( (2 -
the 3
maximum hile glucosidase of ( -
specified bounds final final W α -
eraction studies etc., other bounds that are differen max The applicant explained thatthe most relevantpharmacokinetic parameter toassesss aclinically meaningful change is AUC
applicant used th used applicant basisas the the renal insufficiency including those requiring hemodialysis those requiring including renal insufficiency i mg/day) 100 (maximum dose clinical Japanese each other ( other each glucose 3 once daily once (a) follows: as responded The applicant treated with with treated ofpoint view: a pharmacokinetic from Although there is no problem with referring to the results ofresults F the to with referring no problem is there Although evaluating overseas and Sitagliptin 0.5 as ratio mean geometric AUC the for change meaningful clinically a of lack for studies pharmacokinetic mode of action, PK/PD coadministration of Sitagliptin and Sitagliptin of coadministration with observed changes pharmacokinetic dose (a) Therefore be avoided should 4.(ii).B. 4.(ii).B. with severe renal insufficiency renal severe with int bioequivalence acceptance the in ranges specified (as insert. pre 1124004 dated November 24, 2006 24, November dated 1124004 covariates for a for covariates spectrum bacterial there no major were However, assessed eff the account into taking values, parameter the of deviations individual about inquiries made study and other clinical studies, etc. were set forassessment. checked PMDA the rationale for these ranges C
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page60
, ; 4 is - max the the but etc. and
of a , C
in the the in of
T1 and mg 200 ly when dose herefore
- However, Sitagliptin Sitagliptin etc. , a cyclosporine Sitagliptin Sitagliptin with post , increase in increase
after
. As a experiments
hypoglycaemia hypoglycaemia appropriate hours the
max
, C predominantly renally fect on theAUC 1.4
≤ in vitro the
hypoglycaemia
values of these drugs except except drugs of these values
in
was administered. T was administered.
. 50 . , taking account of the results of of results the of account taking , IC mediated Sitagliptin uptake were were uptake Sitagliptin mediated had no ef - gp has no clinically meaningful effect meaningful no clinically has -
when coadministered coadministered when he P percent inhibition of plasma DPP plasma of inhibition percent values of Sitagliptin for hOA for of Sitagliptin values adverse events of events adverse
evaluated , 50 ) is required 6 study results IC
Since Sitagliptin has a wide safety margin safety wide a has Sitagliptin Since how to how manage result, t
needs to be monitored needsto bemonitored were
. increase increase voglibose
P04 3 concentration monitoring concentration ( The
. distribution of completion before the As a over over a concentration range of 0.1 to 500 μM substrate for for substrate
.
24% with has been confirmed. Sitagliptin does not inhibit does not Sitagliptin has been confirmed. in vitro in
60 hO AT Sitagliptin of Sitagliptin pharmacokinetics the in changes the tration with Sitagliptin was was Sitagliptin with tration Sitagliptin is unlikely to to unlikely is andSitagliptin unbound concentrations concomitant medications were were medications concomitant
uptake AT3 and
or was a was
increase in the AUC of a concomitant drug of a concomitant the AUC in increase O
showed no meaningful increases in Sitagliptin plasma plasma Sitagliptin in increases meaningful no showed max In this study In max
C , Sitagliptin is unlikely to have a marked effect on on effect marked a have to unlikely is Sitagliptin , respectively, which were higher than higher were which respectively, ies hO AT 1 ,
cidofovir uptake
- . Based on the data the on on theBased . cimetidine coadministration coadministration - H
, 3 s response that s response
H
row therapeutic window therapeutic row ’ . 3 .
etc. 160 μM The effects of various drugs on hOdrugs various of The effects AT 3 cells expressing hOAT3. hOAT3. cells expressing is coadmin following similar
. for Sitagliptin Sitagliptin for adjustment no dose , max plicant K1 and t -
also with a nar a with μM
, takingprobenecid account of the was did not inhibit not did
isoforms. Although Sitagliptin is a is Sitagliptin Although isoforms. , taking account , taking problems relevant clinically are not studies interaction drug
were higher than their C their than higher were
. Therefore (about 1 μM) the digoxin that probenecid indicate and literature reports drugs; involving involving interactions 2) Drug analysis of clinical stud clinical of analysis .
. The median
digoxin in change maximum dose digoxin plasma points for sampling of general accepted the the ap accepted (2) asked the applicant to explain the reason for not conducting a drug interaction study with OAT study interaction a drug conducting not for reason the to explain applicant theasked
K
clinically meaningful interactions with these interactions drugs meaningful clinically interactions with substrates for substrates with interactions
PP mg The probenecid
view concentrations despite that about half of the half of about that despite concentrations eliminated it showed weak inhibition of inhibition weak it showed efficacy and safety information safety and efficacy observed inobserved seems a transient change change a transient seems coadministration following CYP of activities with digoxin study interaction the drug concentrations the use of the use Sitagliptin with coadministered cause cause the concomitant drug or caused an up to 78% or caused drug concomitant in 100 PMDA Drug were > 500 hOAT3 follows: as responded The applicant 4.(ii).B. PMDA activity on Treatment Day 3 Day Treatment on activity mg to 200 up of Sitagliptin safety the Japan, (c) In as such inhibitors coadministration for for Sitagliptin (b) package insert. package . Sitagliptin of pharmacokinetics on the investigated using CHO using investigated were not reported despite that a dose higher than the usual dose of 50 mg of dose usual the than higher a dose that despite reported were not or dose reduction adviseto recommend needthere is no result, Sitagliptin result,
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page61
, , ) 100 was **] P046 ) , , careful careful ,
within the the within ** 20
A112 there were 2 there 2 were , drugs insulin secretagogue insulin of action and is glycemic agents agents glycemic
an According to the ( tients with hepatic with tients
A111 . s , * 20** to the results from the the from the results clinically meaningful meaningful clinically glycemic agent glycemic range investigation of drug drug of investigation cases per group per cases
marketing reports, and **
- [ its P013 63 ( the , inhibitor glycemic agent glycemic oral antihyper
A201
126
. until February 2009, until February OAT3 overseas post overseas
marketing information on concomitant on concomitant information marketing - group, comparative study in Japanese Japanese in study comparative group, 2006 did not support support did not - and 5 Japanese phase III clinical studies clinical III phase Japanese 5 and
narrow therapeutic narrow . Sitagliptin has a novel mode has mode Sitagliptin a novel
, data the reference As , phase III clinical studies including a study in in a study including clinical studies III phase
. , Study Number Number , Study 6 drugs, e.g. existing e.g. drugs, who had not received an oral antihyper oral an received not had who A203),
but theybut % 61
and phase I clinical studies including a pharmacokinetic pharmacokinetic a including studies clinical I phase
) and a pharmacokinetic study in pa in study pharmacokinetic a ) and
However 10.0
5.3.5.1.1 - A201
blind, parallel ( clinical study data, study clinical - ( 24 , arget number of cases of of cases of number arget P008 t ( % had who received a single oral antihyper inhibitor, etic profiles or or profiles etic % and <
4 9.0 were submitted were
placebo once daily before breakfast, placebo or Sitagliptin before placebo breakfast, once daily placebo 6.5
. 8 weeks 8 previous the within
≥
and renal insufficiency (P028) insufficiency renal and the applicant’s response concerning concerning response the applicant’s ) al study al of 1C
, 10) - study data study % and ≤
HbA
o 6.0 to
≥
1C 08 - controlled, double in vitr in at present , studies clinical II phase studies clinical I phase Japanese 5 from results the
. is acceptable inhibitors GI], or a biguanide or GI], ,
diabetes mellitus diabetes , - 4 α 5435 , [
2 ) studies were submitted: submitted: were studies ata (i) Summary of biopharmaceutic studies and associated analytical methods and and methods analytical associated and studies of biopharmaceutic Summary (i) ata
OAT 17
ONO- P0 ( ) Early phase II clinic
is needed. Thus, it is necessary to collect post tocollect is necessary it Thus, isneeded. Phase II clinical studies Phase I clinical studies studies clinical I Phase . drugs excreted renally especially , .1
foreign ) ) week oral administration week studies clinical II phase Japanese 2 1 - Summary of the submitted of Summary data .( .(2) .( 8 weeks8 or those with HbA , P055 3 considers as follows: as considers a 2
marketing reports from the launch product reportsin from August marketing glucosidase inhibitor ).A - - α ii Summary of clinical efficacy and safety and efficacy clinical of iii) Summary
Patients on diet and exercise therapy with previous an , P054
medications 4.(i 4.( and drugs for treatment of underlying diseases, and especially when Sitagliptin is concomitantly used used concomitantly is Sitagliptin when especially and diseases, underlying of treatment for and drugs pharmacokin similar with drugs with monitoring 4
4.(iii).A 4.(iii).A - placebo randomized, A type with patients 4.(iii).A See “4. Clinical d Clinical “4. See As the evaluation data evaluation the As . studies clinical I phase from results the for studies” pharmacology of clinical Summary (ii) post information literature of a number with concomitantly used be expected to Based on the submitted submitted Based on the PMDA with interactions drug meaningful to clinically cause unlikely ducted to evaluate the efficacy and safety of Sitagliptin safety and efficacy the to evaluate conducted After on the elimination of Sitagliptin of elimination the on effect reports of concomitant use of an OAT use of concomitant reports with interactions ),P076 ( diabetes mellitus 2 diabetes type with patients following following ( insufficiency renal with patients in study insufficiency
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page62
as rval
in the ).
missing Clinical ( ) .
nalysis of ] a ] data data is shown in
) (% 0 )
0.50 CI
] - .001 corresponding
in the placebo
0 )
value - ) <
P 95% , 0.001 P 0.26, 0.56 0.80,
- [ , group the placebo week w washout week confidence inte confidence [ -
< FAS LOCF as a covariate
[
treatment treatment
Eleven subjects were were subjects Eleven P ( 1C A 6
. including laboratory test test laboratory including Treatment Week [
( treatment difference with with difference treatment
- subjects]; 2 subjects in the the in 2 subjects 5 subjects]; The changein body weight ] .
subjects in in subjects
), respectively ), subjects in the Sitagliptin 100 mg group group 100 mg in Sitagliptin the . weeks 0.84 5 CI efficacy
1 in group the mg 100 Sitagliptin
- 49 of 76 subjects
75 subjects in the Sitagliptin 100 mg mg 100 Sitagliptin the in subjects with no on- no with ( tween 0.6 0.4 ( 75 -
24.1] eek 12 (LOCF) ( 12 (LOCF) eek 95% - for for
1.27, 75 - 17.0] of [ - ) , 2 Least squares mean ( treatment difference with with difference treatment
events adverse
- and baseline HbA and baseline 0.4, 0.3] 39.7, , Change from baseline - . - were as shown in Table 9. Table in shown as were [ subjects [
28.0,
other reasons [ , other reasons
-
[
2.7% as a as covariate and the be and the 12 from baseline to Treatment Week 12 Week Treatment to baseline from
150
1C ) )
1C
therapy 0.1 kg and ). -
1.04 1.00 difference ( (
62 mg/dL change with corresponding 95% with corresponding change
1 subject] last observation carried forward carried observation last ) excluding 1 subject 1 excluding
8.09 6.90 was was % 31.9 mg/dL the (
Full Analysis Set 1.05 - )
. - ) and the the between and ofwhich ( 22.5 )
e placebo group ]
- Treatment Week Treatment Week
glycemic subjects] SD ) subjects
(
was 2 0 from from W baseline to Treatment
was was
FAS 76 clinical clinical of incidence the and group mg 100 Sitagliptin the in
LOCF C ) ) ) ( 1 Mean ] 0.2, 1.1 of Least squares mean [ 0.86 0.85 subjects in the placebo group CI cts) 12 3 ( (
antihyper ( as a factor group treatment
difference in difference 76
subjects inth subjects in the placebo group placebo the in ( 7.69 7.54
were imputed via via imputed were 95%
9 subje [
eplacebo group Treatment Week Treatment Week
3.9% consent withdrawal [ withdrawal , consent 75
showing a significant difference between the groups between difference a significant showing Placebo was 0.7 kg was N
, 75 75 inth including Change in HbA
of
treatment treatment . the change in HbA change the endpoint of - treatment groupas a factor andbaseline HbA
8
confidence interval prior oral on prior
44 other reasons [ reasons , other group 0.4] ] 14.9 3.9, 0.84] (
- [ -
the incidence of clinical adverse events was 64.5% was events adverse of clinical , the incidence
100 mg 100 mg vs. Table Table 95% subjects treated including
1.0,
] [3 subjects] between from the study ( the study from efficacy efficacy - 1.27, ] ANCOVA [ -
[ 100 mg 100 [ east squares mean squares east mg/dL etween treatment comparison The Treatment group 12 for breakfast before daily once administered to be orally Placebo Sitagliptin B Sitagliptin were included in the safety analysis, analysis, safety the in included were ) (l ANCOVA 1.05 9.4 0.7 kg 0.7 - confidence interval confidence - was was
subjects in the Sitagliptin 100 mg group mg 100 Sitagliptin the in subjects
he primary he primary LOCF ) group 75 abnormalities 151 the All of in the included were group placebo Sitagliptin required for patients for required discontinued Regarding safety Regarding and Week Treatment to baseline from As to secondary endpoints, the change in fasting blood glucose from baseline to Treatment Week 12 Week Treatment baseline to glucose from blood in fasting the change endpoints, toAs secondary ( T mg values at Treatment Week 12 Week Treatment at values corresponding corresponding group and 58.7% and group group in either subjects 2 at least by reported events adverse Table 8. Table was and adverse drug reactions was was reactions drug adverse 95% covariance
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page63
were ) cellulitis of which ofwhich
exfoliative leading to ),
) ; and and
)
)
, of which 1 case in in case 1 of, which
75 overdose is the number of cases with
of group the placebo (
= .
n ( %
did did not in occur either group
in the placebo group and in and the placebo group
) ) ) ) ) ) ) ) ) ) 17.1 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) group 2 2 1 1 0 2 0
75 ) subjects ( ( ( ( ( ( ( 2 23 4 3 2 2 2 2 1 1 0 0 0 2 2 1
( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (
= 100 mg
(1event) Safety analysis population analysis Safety n 2.7 2.7 1.3 1.3 0.0 2.7 0.0 75 ( 5.3 4.0 2.7 2.7 2.7 2.7 1.3 1.3 0.0 0.0 0.0 2.7 2.7 2.7 1.3 30.7 100 mg myocardial infarction myocardial of subjects
exfoliative dermatitis exfoliative ;
( 16 Sitagliptin 75 ( ypoglycaemia occurred in occurred
H of ) Sitagliptin 75 ).
15 overdose = ) (
( 100 mg group mg 100 ed
t laboratory data and the numerator the and data t laboratory
n
( 76
) ) ) ) ) ) ) including laboratory test abnormalities test laboratory including Laboratory adverse events reported by at least 2 2 least at by reported events adverse Laboratory = 1 2 0 2 2 3 2 (
( ( ( ( ( ( (
. n oup )
(
) ) ) ) ) ) ) ) ) ) ) ) ) ) )
0.0 2.7 1.3 2.7 4.0 2.7 2.7 1 2 27 5 2 0 1 2 0 3 2 2 2 2 0 2 63 20.0% ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (
events) 1.3 6.6 2.6 0.0 1.3 2.6 0.0 2.6 3.9 2.6 2.6 2.6 2.6 0.0 2.6 4 including laboratory test abnormalities test laboratory including 35.5 groups Sitagliptin ( was was
Placebo gr
5 Placebo group
ver.7.0
in both in both
gastrointestinal disorder gastrointestinal was classified as an adverse drug reaction drug an adverse as classified ) was /J observed in 1 subject of the placebo group were classified as as classified were group the placebo of subject in1 observed
group the of placebo subjects
subject of the
of the Sitagliptin 100 mg of the mg group 100 Sitagliptin
MedDRA
),
gastritis
events erious adverse 1
N ), ) subjects S (
ver.7.0 N cellulitis
events Adverse (
. %
/J
75 Sitagliptin 100 mg group and the incidence of laboratory adverse drug adverse drug laboratory of incidence thein group the and mg 100 Sitagliptin and
%
A
increased
21.3% )
increased )
of and ( group Name of adverse event
glycosylated haemoglobin increas haemoglobin glycosylated
2 mmation
GTP Clinical adverse events reported at by least subjects 2 in either group ( ( ; Name of adverse event γ present urine Glucose Glycosylated haemoglobin increased Blood potassium increased increased acid uric Blood count cell blood White increased ALT . and
The number of cases in eachtreatment group refers to thenumber of cases with pretreatment andposttreatment data laboratory MedDR Incidence Incidence 9 . Laboratory adverse events reported by at least 2 subjects in either group (Safety analysis population) analysis (Safety group either in subjects 2 least at by reported events adverse Laboratory . ) Incidence Incidence Stomach discomfort Toothache Hordeolum Hypoaesthesia Upper respiratory tract infla Constipation Back pain Periarthritis fibrillation Atrial caries Dental rhinitis Allergic Nasopharyngitis Headache Gingivitis Diarrhoea Gastritis 10 subjects cellulitis 100 mg 100 subjects of the placebo group ( of placebo group subjects the Table. Table. 75 were reported were Table headache and and subjects
of
; ] 9 inuation were reported inreported 3 were inuation ( As gastrointestinal symptoms, symptoms, gastrointestinal As 76
of
The denominator is the number of cases with pretreatmentand posttreatmen abnormal changes as judged the by investigator. 13 relisted
subjects in either group were as shown in Table 10. Table in as shown were group either in subjects reactions was 2.7% was reactions 5 deaths No events adverse laboratory of incidence The
12.0% reported inreported 3 ( dermatitis . group discont [ . reactions drug adverse exfoliative dermatitis exfoliative the Sitagliptin Sitagliptin the
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page64
, . 2 ) 1C is 25 68 ) was , and , and **] ) HbA p within the consent
, LOCF (
ptin 25 mg 25 mg ptin ory adverse for efficacy for 100 mg
compared to to compared ). ,
insulin secretagogue 1C
FAS subject] an (
. glycemic agent 1 50 mg 20** to 20 *** , cases per grou per cases *** Sitagliptin or placebo [ 70 therapy , 25 mg , glycemic agent glycemic A202 350
subjects in the the Sitagli in subjects glycemic 80 indicated that thein reductions that indicated
group, comparative study in Japanese Japanese in study comparative group, to Treatment Week 12 Week to Treatment baseline - antihyper subjects in the Sitagliptin 100 mg , group 100 mg thein Sitagliptin subjects groups laboratory adverse event [ event adverse laboratory from from who had not received an oral antihyper oral an received not had who
subjects in the placebo group, lack of efficacy [ of efficacy lack group, inthe placebo subjects 70 1C
% 5 ,
dose dose (
64 bA 10.0
subjects in the Sitagliptin 25 mg group, lack of efficacy oflack efficacy group, 25 mg in Sitagliptin the subjects blind, parallel , Study Number Study , 5.3.5.1.2 - ( 3 arget number of cases of of cases of number arget
e study subject in the Sitagliptin 50 mg group, laborat 50 mg in Sitagliptin the subject t % and < oral antihyper oral single a received had who % ( were included in the safety analysis and the and the analysis in safety the included were
1 6.5 6 9.0
≥
1C the Sitagliptin Sitagliptin the . , group in placebo the subjects
subjects]; HbA % and ≤ significant reductions HbA in reductions significant provided all doses at
73
3 Sitagliptin of Sitagliptin safety and efficacy, response, ( subject]; subject]; 6.0 -
≥ 1 [ 1C II clinical study study clinical II
dose controlled, double clinical adverse event adverse a clinical group, mg 200 Sitagliptin the in ; 1 subject endpoint of the change in H in change of the endpoint Sitagliptin
. . 11 were similar were 50 mg ) within the previous 8 weeks 8 previous the within ) comparisons among comparisons subjects treated subject] s reason other Late phase) Late 1 , .2 subjects in theSitagliptin 50 mg group 363 subjects in the Sitagliptin 100 mg a group, 100 mg the in Sitagliptin subjects consent withdrawal [ withdrawal consent placebo once daily before breakfast before daily once placebo of oral administration week - weeks or those with HbA with those or weeks
ses of ≥ 2 .(2) 8 72 a 2 prior oral oral on prior patients for required was washout week - subjects] GI, or a biguanide or GI, - efficacy efficacy primary he Patients on diet and exercise therapy with α previous 2
shown in Table shown Table in the do at the 6 T
patients with type 2 diabetes mellitus diabetes 2 type with patients
4.(iii).A - placebo randomized, A 200 mg once daily 200 mg After After placebo, while conducted to evaluate the evaluate to conducted orally administered once daily before breakfast for 12 weeks. weeks. 12 for breakfast before daily once administered to be orally was ormg 200 100 50 mg, mg, mg, A 6 the All of , group subjects], subjects], Twelve subjects were discontinued from th from discontinued were subjects Twelve ) group mg 200 Sitagliptin the in subjects [ events; events; [ withdrawal
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page65
of and
50
in the the in in the (
18.8%
) ) ) CI]
First, a linear a linear First,
0.52] 0.82] 0.79] 0.86]
sided - - - - ) ) -
that there was a was there that ) ) ) ) ) ) ) ) ) ) 95%
[ 68 3 3 3 2 2 2 1 1 4 0 group 12 73.5%
( ( ( ( ( ( ( ( ( ( ( ), subjects one
0.001 0.001 0.001 0.001
－
= ( )
0.85, 1.16, 1.14, 1.21,
subjects < < < < ) in the placebo - - - - subjects n
squares mean [ [ [ [ 4.4 4.4 4.4 2.9 2.9 2.9 1.5 1.5 5.9 0.0 (
-
70 P P P P 17.6
and Placebo group Sitagliptin
68 FAS
value 200 mg 200 72 ( - of vs. 0.69 0.99 0.96 1.04 Sitagliptin groups - - - - Least P difference of 5 of ( to be performed.
8
in the Sitagliptin 50 mg mg 50 Sitagliptin the in
(
) ) ) 47 was ) ) ) ) ) ) ) ) ) ) ( ) population analysis afety )
(LOCF) (LOCF) 70 2 2 23 3 0 1 0 4 3 3 0 group
( ( ( ( ( ( ( ( ( ( ( (s % 7.1%
, group placebo the in as a as covariate ( =
] inear ) ) n
1C 2.9 2.9 4.3 0.0 1.4 0.0 5.7 4.3 4.3 0.0 ( 0
11.8%
32.9
0.29] 0.59] 0.56] 0.64]
Sitagliptin - - - - 39 of 73 subjects 0.40
100 mg group, 100 mg A model 100 mg 100
subjects 1
CI] ( 65.3%
1 1 3 1 1 and 1 1 1 % - 1 0 1 2 0 1 - 1 0 1 0.52, 0.83, 0.81, 0.89, 0.16, - 72 , - - - - - [ 3 3 squares mean [ [ [ [ 95%
contrast
-
2 2 subjects - [
), subjects -
the lowest dose with a significant difference was to be be to was difference significant a with dose lowest the
st of
) ) ) ) ) ) ) ) ) ) ) ) 0.28 0.41 0.71 0.69 0.76 73 , group 72 3 0 16 3 0 3 0 2 1 2 1 72 - - - -
Lea group ( ( ( ( ( ( ( ( ( ( (
test excluding thehighest dose group wasbe to repeated.
Change from baseline 14 = Treatment Week Treatment Week
( ( Coefficients of the l of of n
4.2 0.0 4.2 0.0 2.8 1.4 2.8 1.4 4.2 0.0 ( 22.2
8 Sitagliptin 3 ( 50 mg (
group any in subjects of
) 12
in the Sitagliptin the in
19.4% as factors and baseline HbA baseline and factors as
65
4.2%
11.0% ) ) 1.24) 0.82) 0.90) 0.80) 0.94) ) ) ) ) ) ) ) ) ) ) ( ( ( ( ( status
) basedthe on above ANCOV
80 16 1 0 0 3 0 2 6 0 3 3
group ( ( ( ( ( ( ( ( ( ( (
=
) n 7.11 8.04 6.87 6.85 6.88 1.3 0.0 0.0 3.8 0.0 2.5 7.5 0.0 3.8 3.8 ( ) subjects 20.0
Sitagliptin from baseline to Treatment Week 12 Week Treatment to baseline from
25 mg Treatment Week Treatment Week
) (% ) 1C ), subjects 70 SD Clinical adverse events reported by at least 3% of subjects in any any in subjects of 3% least at by reported events adverse Clinical (
of
80
50 mg 25 mg in the Sitagliptin 25 mg the Sitagliptin in 0
200 mg 100 mg
) ) in the Sitagliptin 100 mg group mg 100 Sitagliptin the in
of
46 ) ) ) ) ) ) ) ) ) ) Mean ( ) . 73 1 3 1 0 1 3 5 17 2 0 0
( ( ( ( ( ( ( ( ( ( ( 6
= (
0.84) 0.80) 0.82) was performed and if there was a significant difference, it would be determined be would it difference, significant a was there if and performed was n (0.93) (0.82) ( ( (
closed testing procedure testing closed 1.4 0.0 1.4 4.1 6.8 1.4 4.1 2.7 0.0 0.0 (
Doses included in the current step current the in included Doses ver.8.0 s 23.3
(
a
/J Placebo group 7.74 7.49 7.57 7.56 7.65 subjects) 65.7% Change in HbA 7.5%
subjects group .
, respectively. respectively. , Treatment Week Treatment Week ), ) the Sitagliptin 25 mg , group mg 25 Sitagliptin the 80 11
70
in MedDRA Placebo to Sitagliptin Placebo to Sitagliptin
of Placebo to Sitagliptin Placebo to Sitagliptin , ects
of ) ) dose groupprior and therapy (diabetes)
N t the incidence of clinical adverse events was 53.4 was events adverse of clinical , the incidence 80 72 70 68 73 N Table Table (
iratory iratory
y 46 12
( subjects subj ( %
even in the Sitagliptin 200 mg group and the incidence of clinical adverse drug reactions was reactions was drug adverse clinical of incidence and the group mg 200 thein Sitagliptin Linear Contrast Test 12. Clinical adverse events reported atby least 3% g abnormalg
%
73 68 including
subjects sopharyngitis *
Name of adverse of
Headache pain Abdominal upper tract inflammation tract Hypoglycaemia rhinitis Allergic Eczema Feelin Pharyngitis Hypertension Constipation Na Upper resp Table Table 57.5 17.1% 80 Incidence Incidence 3 1 of tepwise linear contrast test ( test contrast linear tepwise group ( Stepwise (
Treatment of A s 100 mg 100 Sitagliptin mg 200 Dose response analysis Placebo Sitagliptin 25 mg Sitagliptin 50 mg Sitagliptin
) subjects contrast test including all 5 all including test contrast ANCOVA * difference between the placebo and highest dose groups and a linear contrast contrast linear a and groups dose highest and placebo the between difference dose effective minimum the as identified This procedure was to be repeated until no significant difference was observed and observed was difference significant no until repeated be to was procedure This
15 were as shown in Table 12. Table in shown as were group 1.5% was events adverse laboratory of incidence The Regarding safet Regarding
( , group 68 4.1% , group Sitagliptin 50 mg , group mg 50 Sitagliptin
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page66
, , , , ) ) ] 68 73 70 and was were
0.0% of of of ),
) in the , )
2 within the 2 (
3 (
(0 of 70 (0 of 70 (
) increased
cases in the
) ) ) ) ) 2.9% 3 68 3 1 0 0 group subjectsof the
insulin secretagogue ( ( ( ( 4.3% AST
) subjects = (
, Study , Study 5.3.5.1.3 2 an n ( ( 4.4 1.5 0.0 0.0 ( 1 of 73 subjects and
[ glycemic agent Sitagliptin The incidence of The of incidence - 80 200 mg 200 and , group
of cases per group group )
1
( . ctions was 2.7% ) e present urin protein 20 oris
) ) ) ) roup ( 70 3 1 0 0 g ), subjects
( ( ( ( %
Safety analysis population analysis Safety = glycemic agent glycemic
(diarrhoea (diarrhoea n e incidence of gastrointestinal of gastrointestinal e incidence 4.3 1.4 0.0 0.0 ( 70 1.3 in the Sitagliptin 200 mg group mg 200 Sitagliptin the in
were classified as adverse drug drug adverse as classified were Sitagliptin
) group , and , and disease heart hypertensive 100 mg 100 Th of lowering effect . 1 -
( ngina pect ngina . discontinuation
, which was also reported as a serious as a serious reported also was which ,
a
) (
t received an oral antihyper
) ) ) ) ) group including laboratory test abnormalities laboratory including 72 0 2 4 3
( group group, comparative study in Japanese Japanese in study comparative group, ( ( ( ( subjects
100 mg 100 mg - =
1.4% group mg 100 in Sitagliptin the n
0.0 2.8 5.6 4.2 ( , 68
Sitagliptin event) % 50 mg of glucose of (nausea [1 of 80 subjects], diarrhoea [2 of 68 of 68 [2 diarrhoea subjects], 80 [1 of (nausea including laboratory test abnormalities test laboratory including 1
who had no had who
200 mg 200 0.0 in the Sitagliptin 50 mg group, the 50 mg in Sitagliptin 3 % of subjectsin group any (
events required special treatment and their causal causal their and treatment special required events
(
% 3
,
, failure cardiac in placebo group the
)
66 ) ) ) ) se subjects) 10.0 80 2 7 0 0
1 case in the Sitagliptin 50 mg Sitagliptin the in case 1
group
( ( ( (
= , , placebo group the in
group ( group 72 n
2.5 8.8 0.0 0.0 blind, parallel ( 1.4% - events Adverse
Sitagliptin arget number of cases of 60, of cases of number arget of 25 mg ) subjects . t mia ischae myocardial
chronic Evaluation ( % and < ( oral antihyper oral single a received had who % ( 6 -
was
(
7
6.5 50 mg 50 mg 72 9.0 )
)
] ≥
(vomiting [1 of 80 subjects], diarrhoea [2 of 80 subjects]) 80 of [2 diarrhoea 80 subjects], of [1 (vomiting ) ) subjects
1C of ) ) ) ) 73 group 0 2 1 1
8.3% ( ( ( (
but none of the
3 = 73 1 subject of the Sitagliptin the Sitagliptin of 1 subject
as denied ( HbA (0 of 72 subjects) % and ≤ events) ), n
),
0.0 2.7 1.4 1.4 ( ),
6.0 of
ver.8.0 4 diarrhoea
Placebo group ≥ *** 20** , Serious adverse events ( events adverse Serious /J 2
1C 1 case in the Sitagliptin Sitagliptin the in case 1 ( 4.2% .
controlled, double subjects
Laboratory adverse events reported by at least 3% of subjects in any group group inany subjects of 3% at least by reported events adverse Laboratory overdose ** to iabetes mellitus diabetes . increased
80 MedDRA 2.7% in the Sitagliptin 200 mg group mg 200 Sitagliptin the in case in the placebo group placebo the in case ,
vomiting 0 mg group 0 mg 1 of resolved without discontinuing the study drug study the discontinuing without resolved N) Laboratory adverse events reported by at least study drug study after of which resolved all ( (
increased .
ased GTP
3 *** 20 was was ( % event ) within the previous 8 weeks 8 previous the within ) γ 13 [ Phase II clinical study II clinical Phase
4.4% all ), , CK incre ) increased
were reported were cases Name of adverse , nausea .3 Table ( but and 3.8% 6 , but a causal relationship to the study drug was denied for all cases for denied was drug to study the relationship a causal , but Protein urine present urine Protein Blood ALT AST in the Sitagliptin 100 mg and 4.4% group, 100 mg thein Sitagliptin A203 , , , respectively ,
Incidence Incidence .(2) 8 weeks or those with HbA with those or weeks 8 in the Sitagliptin 25 mg group increased
GI, or a biguanide or GI,
- Patients on diet and exercise therapy with α previous 50 mg 50 mg of the Sitagliptin in 1 subject were observed to discontinuation eading
3.8% symptoms symptoms in the Sitagliptin 5 Sitagliptin the in subjects) subjects]) Sitagliptin 100 mg , group mg 100 Sitagliptin reactions of which of which ) subjects ) subjects were as shown in Table 13. Table in shown as were adverse event adverse hypoglycaemia Sitagliptin 25 mg , group 25 mg Sitagliptin 1 subject of the Sitagliptin 200 mg 1 subject of Sitagliptin the patients with type 2 type with patients 7 4.(iii).A Number - placebo randomized, A
), subjects deaths No l ALT
rea drug adverse laboratory of incidence the and group mg 200 Sitagliptin reported in 1 subject of the Sitagliptin the of subject 1 in reported Sitagliptin 200 mg ( group 200 mg Sitagliptin ; ischaemia myocardial w drug the to study relationship
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page67
1 of .d. on ,
, group group) group)
] ] ] )
, both for
.d. 3.2 group who ue 22.4 28.9 q.d. - - -
the study (1 CI for for CI 0.001 0.146 0.001 50 mg b.i 50 mg
PPS)
mg/dL val ( ( - < = < tablets before
%
) P squares mean 14.8, - P P P 0 34.7, 40.9, - 0.001 95 - - [ 3 [ [
0.146). ( itagliptin 100 mg 100 mg itagliptin
< least who took incorrect took who =
P P
( (
Sitagliptin Sitagliptin Sitagliptin 100 mg once mg 100 Sitagliptin “
discontinued
tablets before breakfast before tablets
Treatment Week Treatment Week
group and the Sitagliptin 50 the Sitagliptin and group ] ]
( 3 squares ] 9.0 - (
28.6 34.9 - - - mean who who 2.3
11.1 17.5 CI
- -
. Least subjects in the S the in subjects placebo, and 2 subjects hour weighted mean glucose as a a as glucose mean hour weighted 95% 15.0,
- 28.0, 34.2, [ - - [ [ 27 hted mean glucose from baseline to to baseline from glucose mean hted
twice daily ( daily twice
) ) )
were included in the safety analysis, analysis, safety the in included were
100 mg q.d. 100 mg
)
14.8 29.1 receive receive 19.7
( ( group and Sitagliptin 50 mg b.i 50 mg and Sitagliptin group
(
SD
week washout was required for patients patients for washout required was week before meal before daily twice ( - Mean
Change from baseline subjects in the Sitagliptin 100 mg mg 100 Sitagliptin in the subjects 8.5 50 mg 27.5 36.5 - - - ) group A 6 hour weig 25 -
1 subject in the Sitagliptin 100 mg q.d.
.d.
;
.i excluding 2 subjects 2 subjects excluding
67 hour weighted mean glucose as covariate a ) ) )
- )
6.4
4 19.5 25.9 - - - . weeks 36.7 33.8 37.4 ) squares mean ( ( ( -
difference 4 Week group . analysis efficacy primary ) for Treatment Least Both the Sitagliptin the Both 162.1 161.1 182.8 for for lowering effect of Sitagliptin of effect lowering , or Sitagliptin Sitagliptin or , - ) .d. ) placebo twice daily before meal before meal daily twice placebo ) (mg/dL ) .i
orally administered administered orally 14. was performed. was groups between
SD ) ) ) s (
, group the in placebo subjects 0 ” group 50 mg 47.4 57.0 41.6 ( ( ( group as a factor and baseline 24- baseline and factor a as group
to be Mean 28
( hour weighted mean glucose from baseline to Treatment Week 4 Week Treatment to glucose baseline from weighted mean hour
subjects were randomized to randomized were subjects 50 b mg
Week lack of efficacy of due to lack therapy. therapy.
Treatment
189.6 197.6 ), 191.3 Per Protocol Set Protocol Per (
of comparison
Sitagliptin
Placebo Placebo
endpoint of the change in 24 change the of endpoint , group placebo in the subjects
vs. N 24 25 27 vs.
vs. PPS
. 27 d glycemic 100 mg q.d. 100 mg is shown in Table in is shown . ( q.d. i . q.d. Change in 24-
omparisons subjects in the Sitagliptin 50 mg b mg 50 Sitagliptin the in subjects : twice daily twice : b.i.d. there was no significant difference between the Sitagliptin groups Sitagliptin the between difference significant no was there
14. treated subjects ,
tablet before evening meal evening before tablet
. 100 mg 100 mg 50 mg b 25 d . group had significant reductions compared to the placebo group placebo the to compared reductions significant had group 80 1 i week oral administration of oral administration week subjects q.d. antihyper
- , ), but and study drug was drug and study
Table Table Sitagliptin Sitagliptin efore evening meal evening efore
.d. ) 76 “ from baseline to Treatment Week Week Treatment to baseline from glucose blood in fasting change the of endpoints secondary he a 2
( .i : once daily Treatment group oral , group o adjustment for multiplicity Sitagliptin Sitagliptin Sitagliptin b.i.d. Sitagliptin 100 mg Sitagliptin 50 mg b. c group Between Placebo subjects in the Sitagliptin Sitagliptin the in subjects q.d. ANCOVA including treatment groupas factor a andbaseline ANCOVA 24 N
efficacy efficacy primary he mg b ANCOVA including treatment including ANCOVA covariate As to t
T the All of glucose blood the to evaluate conducted After 4 Week Treatment tablet b tablet daily ” group which breakfast q.d. 24 prior could not continue to take study drug due to spoiled study drugs) study due to drug spoiled study take to could continue not were included in the subject in the placebo group q.d. mg 100 in the (1Sitagliptin subjectdrug each study
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page68
. 0.915 0.012 0.009
] ] value ] - = = =
P P P P
1.8
) 22.5 21.9 - ] ]
- -
) ]
CI]
17.0 10.6 CI 2.0
. - -
23.6,
mg/dL 45.7, 44.6, - , 0.101 0.001 0.001 PPS - - (
[ value
squares mean
[ [ ( 95% squares mean -
) = < < -
[ - 8.2,
7.7 95% P 0 -
)
P P P ] 2 21.4, [ but there was ] ]
- - ) in subjects 12.7 [ [ 34.1 33.2 group and the the and group -
- - Least 4.7 5.5 in placebo the
CI] - - 17.1 PPS
)
( for leastfor
0.9 20.5 21.4 Afterevening meal 4 - - squares mean 95% 36.3, 37.3, - 15.4, [ difference - - - [ [ 4 of 25 [ (
Least Treatment Week
N 27 24 25 (
subjects
]
]
] squares 3.1
- ent Week ent Week 22.3 16.0 - - - mean 5.4 q.d. mg 100 1.3 11.9 CI -
-
of 28
Least
4
95% 13.9,
20.4,
( - ] ] 26.6, - 0.083 0.001 0.027 ] [ - [
value [ - = < = %
as a covariate as
) ) 5.1 P
)
20.6 33.7 - P P P - -
) CI] 22.2 17.3
14.5 14.3 ( ( (
SD
24.6, ( Change from baseline 41.4, 54.0, - Mean - -
[ squares mean
[ [ 95%
3.3 - [ 22.9 15.2 - - - , and 16.0% q.d. group
(the same ANCOVA model as in the primary the primary as in model ANCOVA (the same
]
14.8 ]
] blood glucose
31.0 43.9 mean - - -
Least blood glucose (breakfast, lunch, evening meal) meal) evening lunch, (breakfast, glucose blood
After lunch 4
1.9 1.7 15.0 CI] -
e
-
) ) )
both the Sitagliptin Sitagliptin the both
12.9 29.1 16.2 - - - 68 , squares 95% 27.5, prandial 6.3 100 mg ) 30.4, - 27.1 29.5 29.9
[ 12.9 19.3 - - - 43.1, difference - ( ( ( - - [ - [
squares mean [ ) -
16
differenc was performed.was blood glucose from baseline to Treatment Week 4 Week Treatment to baseline bloodfrom glucose
prandial N Least 27 24 25 - 137.8 141.4 156.5 Least was performed.was hour post hour Treatment Week Treatment Week
-
Table Table mg/dL( )
(
prandial
0 ] ] SD -
0.163 0.001 0.001 4 (
]
value
) ) ) - = < <
hourpost P
30.6 42.7 3.1 P P P - -
s between groups between s 2- 41.9 42.1 29.8 CI] Mean in the Sitagliptin Sitagliptin in the ( ( (
) , group the to placebo compared reductions significant had 19.6, 54.6, 66.3, - - - 50 mg b.i.d. s between groups between s [ hour post hour
squares mean [ [ 95%
- - [ ] ]
160.7 156.5 159.8 and a causal relationship to the study drug was denied for all events all for denied was drug study the to relationship causal and a group ]
.5 8.2 - between the Sitagliptin groups Sitagliptin the between
Treatment Week Treatment Week 42.6 54 4.9 29.9 17.9 CI] - -
Least
- - group
Change in fasting blood glucose from baseline to Treatm to baseline from in blood glucose fasting Change After breakfast
subjects of comparison
11.9 46.3 34.4
- - - Placebo Sitagliptin Placebo N squares mean 95%
25 24 27 28.7, comparison - [ - 62.7, 50.9, 15. difference [
- -
vs. [ [ vs. vs. of
. Change in 2 was was events adverse clinical of incidence , the N
24 27 25 Least eatment groupas factor a andbaseline fastingbloodglucose ascovariate a
q.d. q.d. q.d. 4 of 27 50 mg b.i.d. b.i.d. b.i.d. Table Table omparisons and the change thein change and 16. ( )
50 mg b.i.d. 50 mg
50 mg 100 mg 100 mg 50 mg 100 mg 15
Table Table gliptin
50 mg50
100 mg 100 mg
Sitagliptin
nt group Treatment group
q.d. Table Table
( b.i.d.
Sitagliptin Sitagliptin Sitagliptin Sitagliptin c group Between Sitagliptin Placebo o adjustment for multiplicity vs.
17 Table in shown as were group any in subjects 2 least at by reported events adverse Clinical difference significant no , 14.8% group Sita the Sitagliptin analysis) efficacy Regarding safety Regarding ANCOVA including tr including ANCOVA N from baseline to Treatment Week Week toTreatment baseline from 4
Placebo Placebo
Treatme omparisons o adjustment for multiplicity Sitagliptin q.d. 50 mg vs. Sitagliptin b.i.d. vs. c Sitagliptin q.d. 100 mg Sitagliptin 50 mg b.i.d. group Between Placebo Sitagliptin ANCOVA including treatment groupas factor a andbaseline ANCOVA 2 N
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page69
, , ; d 1 50 up (
- were ) ) subjects vomiting group ha group ,
) 28 ypoglycaemia 1 event in 1 event the There were no H of , . )
2
nausea ) ( ) ) ) ) ) ) 50 mg
in the Sitagliptin 50 Sitagliptin the in 25 0 0 0 1 0 1
( ( ( ( ( ( group
= )
. ) 50 mg b.i.d. n
0.0 0.0 0.0 4.0 0.0 4.0 (
) b.i.d. ) ) 50 mg due to a suspected mix suspected a to due 25 1 2
( ( group blood uric acid increased uric acid blood Sitagliptin
= (
n subjects 4.0 8.0 ( , 3.7% group in placebo the
) b.i.d. Safety analysis population analysis Safety (
25 Sitagliptin
Laboratory adverse events were as as were events adverse Laboratory
of ) .
) ) ) ) ) ) 50 mg 50 mg Sitagliptin the and in 1 event 100 mg 2 27 1 0 0 0 0 0
( ( ( ( ( ( (
group =
testinal symptoms ( symptoms testinal
0
n
3.7 0.0 0.0 0.0 0. 0.0 (
event) and 2 subjects of the Sitagliptin the of subjects 2 and event) )
q.d. 00 mg ) ) 1 1 27 1 1
. to discontinuation leading
( ( 8.0%
group = jectsin group any Sitagliptin
) Safety analysis population analysis Safety n 3 of 28 subjects 3.7 3.7 ( ( ( including laboratory test abnormalities test laboratory including
Gastroin
q.d. red blood cell count decreased count cell red blood oup ( and and , respectively , 1 subject in the Sitagliptin Sitagliptin the in subject 1
gr
Sitagliptin
69
) adverse drug reactions was 7.1% was reactions drug adverse ) ) ) ) ) ) 28 1 1 1 1 0 1
( ( ( ( ( (
, group =
n
3.6 3.6 3.6 3.6 0.0 3.6 ( ) subjects )
) ) 28 2 0
Placebo group ( (
25 = ver.8.0
100 q.d. mg n 7.1 0.0 ( /J
laboratory of were classified as adverse drug reactions drug as adverse classified ) were
1 Placebo group
(
ver.8.0
/J %
), decreased red cell count blood
MedDRA these cases were reported as overdose overdose as reported were cases these of all (
),
4.0 N Serious adverse events ( events adverse Serious (
. Laboratory adverse adverse events 18. Laboratory
. d increased % MedDRA and , group , and , and decreased haemoglobin N) ), Name of , ( group the of placebo events in 2 subjects Four Table Table
asopharyngitis adverse event .Clinical adverse events reportedby at least 2 sub % Overdose N events) and events) 17 Incidence Incidence 18. 2 including laboratory test abnormalities test laboratory including Name of adverse event ( in the Sitagliptin 100 q.d. mg Sitagliptin the in . group placebo the of subject in 1 subjects ed blood cell count decreased count cell blood ed Table
Urine ketone body present body ketone Urine R increased acid uric Blood decreased Haematocrit Haemoglobin decreased White blood cell countincreased blood uric aci uric blood Incidence Incidence were reported were ( 27 100 mg q.d. 100 mg incidence of of incidence the roup and g group ( group . group in any reported not ) were in 1 subject of the Sitagliptin the of 1 subject in of 1 ) subjects (
reported
b.i.d. b.i.d. 27
unblinding revealed that only the that only revealed unblinding but drug, of study mg No deaths No observed the protocol by specified dose of as Sitagliptin the maximum ataken dose exceeding The incidence of laboratory adverse events was 10.7% was events adverse of laboratory incidence The
was was adverse events events adverse diarrhoea of mg 3.7% shown in Table shown in Table haematocrit decreased haematocrit Sitagliptin Sitagliptin b.i.d. group
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page70
, * 8 4 [
** was was oral [
) ) in the the in within the
subject] hasbeen prior above the
1
confidence confidence group
fell subjects in the the in subjects
insulin secretagogue subjects in the the in subjects 8 95% an ( (
glycemic agent voglibose for primary efficacy efficacy for primary oglibose
155 v ( data treatment cases per group per cases ( compliance with study compliancestudy with
- and the results based results the on and
subjects in the voglibose subjects ] subjects in the Sitagliptin Sitagliptin the in subjects
treatment difference in the the in difference treatment clinical adverse events [ events adverse clinical 155 non
e safety and and e safety th and evaluate glycemic agent glycemic 17 once daily before breakfast daily once
156 163 subjects
,
( , 0.57 corresponding 310, confidence interval confidence - no on with
moving out of the area [ the outarea of moving subjects in the Sitagliptin group Sitagliptin the in subjects 301 0.30 , [ 8
, 50 mg ( P054 Number , Study 5.3.5.1.4 )
oral antihyper oral 95% ( ], subjects 6 ] % [ before each meal each before subjects
no evaluable data at Treatment Week 12 Week at Treatment data evaluable no 0.44 controlled, comparative study in Japanese Japanese in study controlled,comparative just - 318 subjects]
from baseline to Treatment Week 12 is shown isshown 12 Week Treatment to baseline from
were included in PPS the were included
2 ) who had not received an oral antihyper oral an received not had who inferiority of Sitagliptin to Sitagliptin of inferiority C
was was 1 1 subject1
Sitagliptin
[ %
70 10.0 rval indicated that the- between indicated
HbA f which
excluding 1 subject excluding week washout was required for patients on patients for required was washout week ) O - times daily daily times the non- the
. , and after excluding a further excluding after and )
arget number of cases of of cases number arget A 6 t % and < %who had received a single ( . LOCF
three
6.5 ( group, voglibose group,
8
9.0
-
. ≥
subjects in the Sitagliptin group Sitagliptin the in subjects 0.2% ) subjects in thevoglibose group - lack of efficacy [ efficacy of lack 1C ( , 9 blind comparativestudy weeks -
confidence inte confidence 163 HbA and as the limit of lower the
0.2 mg 0.2
( % and ≤
parallel 12 6.0
≥ 95% treatment difference in the change with with change the in difference treatment
- 1C 5 subjects] oint of the change in change ointthe of subjects]
[ subjects in the voglibose group 2 . subjects]; blind, blind, evaluable data at Treatment Week 12 Week Treatment at data evaluable - HbA 28, 0.51] 9 subjects in the voglibose group in voglibose the subjects voglibose diabetes mellitus diabetes 3 endp ; 0. no ]
[
or ) therapy. 146 nistered for , placebo of oral administration ) efficacy inferiority margin margin inferiority
treated subjects treated Phase III double Phase III compliance with exercise therapy with exercise compliance **] 39%
The between ) efficacy efficacy 0. corresponding subjects in subjects the ) voglibose group Phase III clinical studies clinical III Phase et and exercise therapy with Analysis based on the FAS Analysis based .1 week 319 2 subjects non- ) ) within the previous 8 weeks 8 previous the within ) lack of lack [ 19. 3 Seventeen subjects were discontinued from the study from discontinued were subjects Seventeen
glycemic 2- ,
was *** 20 .( .(3)
were included in the safety analysis safety inthe included were 155 8 weeks or those with with those or weeks 8 a defined non- biguanide - group agliptin a heprimary Patients on di Sitagliptin group Sitagliptin
( conducted to compare the efficacy between Sitagliptin andvoglibose Sitagliptin between efficacy the to compare conducted Sitagliptin of tolerability After After interval or 8 T the All of
20** to double randomized, A 4.(iii).A 4.(iii).A patients with type 2 type with patients pre . confirmed in Table in ) group change with with change previous voglibose group were included in the in FAS included were group voglibose , group Sit orally admi to be orally the FASthe PPS. on based those with consistent were treatment ], subjects , group Sitagliptin . analysis [ e events advers clinical consent withdrawal [ withdrawal consent antihyper subjects]
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page71
, . ), ]
12.2, 12.2, 22.8, blood - - in the mg/dL (1.3% [ [
) increased treatment treatment
- subjects
Laboratory )
] ] 18.8 g/dL .
) , respectively , mg/dL m squares mean % ) prandial 0.62 AST 0.22 CI 163 - (
- -
-
subjects ) and increased % ) ), 0
of
8.9 95 19.6 - 0.78, 0.28, 0.51] 0.39,
156 - - - [ 3
ratory adverse drug drug adverse ratory [ [ 163 [ = cholesterol increased cholesterol
n subjects
( CI for least for CI ) ) The between The
PPS)
) ) of ) ) (
4 5 24 17
hour post hour were were 12 14 ( ( ( ( subjects] ( (
, respectively ,
) 95% (1.2% [2(1.2% of 163 subjects]) ] 6.2, 15.3 1.8% LDL 156 2- in the Sitagliptin group and in Sitagliptin and the group 79
] group [ (
blood TG ), blood 2.6 3.2 (
7.7 9.0 ) as a covariate a as 15.4 10.9 Treatment Week Treatment Week ),
( in of CI 155 Safety analysis population analysis Safety
( 1C
of
41
( oglibose in the Sitagliptin group and ALT and group thein Sitagliptin HbA
6 mg/dL
) subjects 95% V [
) [
squares
] subjects - 0.70 0.30
- - mean increased increased ] subjects )
155 10.7
Least 163 baseline 26.3% 163
3.9%
TG ( = 155
of 0.39 n of
( )
subjects
was
) ) ) ) ) and ) )
of ] 3 of 155 subjects
Change from baseline
5 22 2 4 7 7 ( ( ( ( ( ( 14 11 ) [
( ) ( 4 cholesterol increased
squares mean difference blood blood [ 0.56 0.53
- 163 ( ( 3.1 1.2 2.5 4.3 4.3
of subjectsin either group SD squares mean mean squares
13.5 (
- in the voglibose group and the incidence of clinical of incidence the and group thein voglibose as factors and as factors Mean
71 increased increased 1.9% of ) Least 0.71 0.34
- - LDL ( 9.0% 2 east 2.6% , subjects
were as shown in Table 20. Table in shown as were group either in subjects of l [ status (
( CK
Sitagliptin group from baseline to Treatment Week 12 Week Treatment to baseline from s])
and
) )
163 1C 9
agent
subjects ) 12 9.1
respectively, in the Sitagliptin group and and group Sitagliptin the in respectively, . 1.2% 0.78 0.8 of (
blood blood ( ( , subjects were were subjects
increased . group voglibose the in , respectively, ver
) 156 ), confidence interval confidence 2 Week % 17 ]
increased Treatment ( 7.03 7.45 (
)
of 45.4] subjects 26.5] - SD -
( 95%
GTP in the voglibose groupand theincidence of labo he changes in fasting blood glucose and blood glucose fasting in changes he
101 verse event
MedDRA/J ) ) γ (
163
subjects Change in HbA 0 ,
) ,
blood ALP Mean is 56.5,
tory inflammation tract tory 37.9, N , 0.90 0.84 -
( ( ( - [
of . 19. [
155
%
Week
4 Treatment 64.7% 7.74 7.78 ( Name of ad of Name
of (1.2% [2(1.2% of 163 subject
) subjects
he incidence of clinical adverse events 48.5% was events adverse of clinical incidence he Table Table t 11
mg/dL ,
.Clinical adverse events reported by at least 3% [ mg/dL
Nasopharyngit distension Abdominal Flatulence Constipation Diarrhoea Upper respira corresponding
Incidence Incidence N 2.5% 155 20 155 146 comparison
51.0 of , respectively , - 32.2 7.1% Table - increased Sitagliptin (
26 vs. (
and treatment
CK
and
od cell count increased count cell blowhite od
ween
oglibose ] 10.9, 26.7 16.4] 5.5] increased increased adverse drug reactions was 10.4% was reactions drug adverse and reactions was was reactions Clinical adverse events reported by at least 3% least at by reported events adverse Clinical blood Sitagliptin group and group Sitagliptin 16.8% at least by reported events adverse [ (2.6% [4 of 155 subjects]) 155 [4(2.6% of The incidence of laboratory adverse events was 6.7% was events adverse laboratory of incidence The
Regarding safety Regarding V t of endpoints The secondary Treatment group Sitagliptin Voglibose Bet
- glucose from baseline to Treatment Week 12 Week Treatment to baseline from glucose (1.9% [3(1.9% of 155 subjects]) difference with with difference - ANCOVA includingtreatment groupandprior antidiabeticANCOVA
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page72
. , ) at ), )
] 1C 65 for (no and was
were ) group
during during glycemic HbA )
FAS * 20** SD If
pioglitazone at or after . diarrhoea
±
label phase, label phase, to ; - other reasons other reasons 50 mg , throughout the the throughout phase blind - 9.0% on 9.0% mean mean
( 2 of 156 subjects ≤
clinically relevant relevant clinically adverse events was was events adverse ( week, randomized, randomized, week, ** 20**
. and 4 subjects of the the of andsubjects 4
[
in the voglibose group 140 mg/dL 140
in the voglibose group theinvoglibose double subjects] week open week
) - ) 2 6.0% and
P055 group ≥
1C and Sitagliptin cases in the Sitagliptin group group Sitagliptin the incases ) and 1.3% ) were classified as adverse drug drug adverse as classified were dizziness) 2 s , in group the placebo 68 subjects subjects leading to discontinuation were were discontinuation to leading ; )
arget number of cases of 130, of of cases number arget ] subjects ) abdominal pain upper pain abdominal t
( ;
] 9 156 week and 2 subjects of the voglibose pioglitazone within pioglitazone combination
once daily before breakfast before daily once 155
) subject in the placebo group, lack of in of the lack subject placebo group, of phase and a 40 and phase
14 weeks and not on any other oral antihyper oral other any on not and weeks 14 itus 12
of 1 4 ≥ ( diarrhoea ( 2
distension
within the previous 8 weeks 8 previous the within in the voglibose [
relisted ;
[ cellulitis 2 of 163 subjects including laboratory test abnormalities test laboratory including , cases these Of the dose of Sitagliptin was to be increased from from be increased the to was dose of Sitagliptin Sitagliptin Sitagliptin 2.6% ( (
. , 1.3%
( 1.17 kg 1.17
administered
The incidence of hypoglycemic 72 comparative , Study Number , Study 5.3.5.1.5
leading to discontinuation or to discontinuation leading ( subjects 134 treated . ( blind phase ( phase blind disease s abdominal abdominal - glycemic agent ( .
Subjects were to continue pioglitazone tocontinue were Subjects
is analys and the safety inthe included were . 1 event) , clinical adverse events [ events adverse , group clinical . 16 weeks prior to the start of the of start the to prior weeks 16 0.96 ± orally at a stable dosage for
but a causal relationship to the study drug was denied for for denied was drug study the to relationship causal a but ≥ group, group,
- ), ’ Crohn
- 12 of a consisting pioglitazone, with ; ] to be 50 mg abdominal pain upper pain abdominal or patients with HbA with patients or weeks 8 previous the within ) ( s pioglitazone
relisted as taken at taken as [
ombination study group including laboratory test abnormalities test laboratory including Serious adverse events ( events adverse Serious
), all of12 weeks the ( c blind, parallel blind,
- ( . Crohn’s disease Crohn’s in the Sitagliptin group and and group Sitagliptin the in , or biguanide urine ketone body present body ketone urine there was no safety problem safety no was there ; ) GI dose were permitted) dose - α change in body weight from baseline to Treatment Week 12 Week baselineTreatment to from weight in body change ,
s , and and , at the next scheduled visit scheduled at the next 6.5% and < 10.0% on 10.0% < and 6.5% foot fracture foot
( The ≥ ioglitazone subjects to evaluate the efficacy and safety of safety and efficacy the ) to evaluate 8 weeks and on another single oral antihyper oral single another on and weeks 8 blind phase
in the Sitagliptin group and - group in the Sitagliptin . 1C
P - There was no hypoglycaemiaThere was
a ≥ after Treatment Week 24 or fasting blood glucose was ≥ was glucose blood fasting or 24 Week atTreatment or after ) dose the same at
were reported were . foot fracture foot 163 .2 ). subjects in the Sitagliptin Sitagliptin the in subjects Adverse events Adverse pioglitazone ( group % 100 mg
Four subjects were discontinued from the study the from discontinued were subjects Four 3 label phase (40 weeks) were were weeks) (40 phase label term therapy combination of the safety of
controlled, double s) - .(3) . to 7.0 1.26 kg 3
( insulin secretagogue insulin
( ≥
s long subjects in the Sitagliptin 50 mg ) group 50 mg insubjects the Sitagliptin . events event d 2 cases in the in voglibose d 2 cases Patients with HbA with Patients 2 1 subjects] 0.27 ±
No deaths No reported in 1 subject of the Sitagliptin ( group Sitagliptin in the 1 reported of subject ( all all cases per group per cases the Placebo or Sitagliptin 50 mg during the during double mg 50 Sitagliptin or Placebo was was 9
4.(iii).A Sitagliptin of study combination A placebo- [2 of155 subjects]) was conducted in Japanese patients with type 2 diabetes mell diabetes 2 type with patients Japanese in conducted was group Sitagliptin the of subjects 2 in observed for for dosage a stable - theopen period study 50 mg Treatment Week 16 and Week Treatment agent efficacy changes in in changes For the double efficacy; all of which resolved after treatment discontinuation treatment after resolved which all of voglibose an 66 [ reactions, but were moderate or mild in severity or mild moderate were reactions, but 1.8% - 1.2% was reactions drug adverse of incidence and the respectively hypoglycaemi
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page73
1 er % is by as a )
and
five
- 1C blind blind ) - 35.0
consent consent
) test ,
- LOCF subjects]; ] as factors as factors % ] (
). in the S/S S/S the in
( 100 mg 100 blind phase phase blind was was
- 8
) ; Treatment ; Treatment Twenty 0 0.27 CI
- .001
. 0 dose increased
value
- ) < status
Treatment Week Week Treatment 95% P 7.0%
( P 0.26, 0.53 0.55, subjects] - [
[ < a paired t a paired
subjects 9 FAS , S/S group (
1C P/S group P/S 40 value at 12 weeks aft weeks at 12 value phase in and the 25 P/S group
Treatment Week or efficacy or are presented in presented are Figure ( 0.001 f
of 1C HbA
as factors andbaseline HbA
on compared to the placebo placebo to the compared on <
(LOCF) (LOCF)
who had their had who an blind group included 63 double 63 included group for the the for
P
( FAS status
] subjects ) S/S
subjects in the in the subjects 0.61 CI
- 40 group, lack of efficacy [ efficacy of lack group,
subjects treated with placebo during with treated subjects during placebo lack of efficacy [ efficacy of lack in the the in 0.41 0.40
, - of squares mean 95% - achieving 1.00, 67 - (
[
31 Change from baseline Least subjects
66 an even lower HbA lower an even 52). inboth groups subjects] from baseline to Treatment Week 12 12 Week to Treatment baseline from 5 the P/S group and 13 P/S group the
subjects subjects the subjects Among 1C
(except pioglitazone for ) )
including including 73 in 12 The dose of Sitagliptin was increased to increased was Sitagliptin of dose ). The
52.
1.16 1.03 133 ( (
) , subjects in the P/S inthe subjects observed
% Week ( 8 Treatment 8.03 7.34 group had a significant reducti had a significant group
(
ere ) subject] , subjects w subjects from baseline to Treatment Week 12 Week Treatment to baseline from
SD 0.81 ) weeks ( subjects treated with Sitagliptin 50 mg during the during double with mg 50 Sitagliptin treated subjects - 1 Treatment Week Week Treatment
C blind phase completers, completers, phase blind ( - subjects in P/S, 42 the group subjects 1 80
) )
40 50 mg
52 66 0 ( of 41 , Mean squares mean difference
0.78 of 0.89 ( - ( (
and the ofproportion subjects 56 Treatment Week Week Treatment
Week ( 15 Treatment Least 7.62 7.73 clinical adverse events [ events adverse clinical group] , from baseline baseline from
) to Treatment Week in 52 the s P/S and S/S group Week )to Treatment subjects
s group double were (Treatment Week 12 Week (Treatment baseline from time over other [ reasons
P/S
Change in HbA
,
with subjects , the of proportion N were included in the safety analysis and the the and analysis inthe safety included were 68 66 group 1C
endpoint of the change in HbA in change of the endpoint s]
). as a covariate including including 21.
10 was 70.0% 70.0% was Placebo ANCOVA including treatment group and prior antidiabetic agent antidiabetic and prior group treatment including ANCOVA ) treatment phase treatment
blind phase withdrawals. phase blind and the Sitagliptin the and S/S 1C
-
term treatment phase phase treatment term 40 in 83 HbA
- 21 Table Table ) group thein S/S in term
double to 100 mg 2 subject
group]
, 0.001
s 50 mg 50 mg vs. 3 blind [ phase
, subjects - treatment <
for the group S/S S/S
P 80 ( seven subjects in the P/S the in subjects seven subjects - 50 mg Treatment group of Placebo Sitagliptin Between Sitagliptin comparison subjects in the 40
ANCOVA including treatment group andprior antidiabeticANCOVA agent covariate
Sixty
efficacy efficacy primary he
28 completers and and baseline HbA and baseline 10 The change T
- long For the 12) and the long - double the for separately performed were analyses safety and Efficacy ( Week 0 Week group shown in Table inshown Table their dose increase increase dose their of the double subjects were discontinued from the study from discontinued were subjects withdrawal [ withdrawal Week Treatment ). group and significant reduction andsignificant phase [ phase 17 from from the effect was maintained until until maintained was effect the
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page74
0.05
≤
P
: Weeks ●
, ) of 68
) 39 0.01 0.01 group comparison of
in the the in ( -
≤
and the
2 P ( including including subjects
lower limb limb lower Within ●●: (
66 57.4% group
was denied for for denied was coronary artery artery coronary coronary artery artery coronary of ( ( increased
4
( ) )
events)
66 50 mg
CK SE
2 =
group ±
n
( events)
6.1%
) ) ) ) ) ) ) ) ) ) ) Safety analysis population analysis ) (Safety /S group 3 9 3 2 2 1 0 0 0 3 2 11 ( ( S ( ( ( ( ( ( ( ( ( (
group and p ) (Mean
50 mg 4.5 3.0 3.0 1.5 0.0 0.0 0.0 4.5 3.0 13.6 ) 16.7 in the placebo group and 7.6% group ) in placebo the grou
blind phase blind Serious adverse events ( events adverse Serious - cts subjects were were subjects . Sitagliptin imputation adverse events was 2.9% was events adverse
in the Sitagliptin
subjects ouble ) subje D (
68 in the Sitagliptin 50 mg group and the 2 2 the and group mg 50 Sitagliptin the in 68
LOCF =
68
n of ) (
) ) ) ) ) ) ) ) ) ) of 3 2 0 2 2 2 2 2 0 0 17 5 ( ( ( ( ( ( ( ( ( ( ( (
5 without without
( ) Change from baseline (% baseline from Change ) ( 4.4 2.9 0.0 2.9 2.9 2.9 2.9 2.9 0.0 0.0
25.0 ) 66 subjects ) subjects
74 FAS ( of
66 Placebo group 38 ( of 2 subjects of the Sitagliptin Sitagliptin the of subjects 2
was was events adverse clinical of the incidence
but a causal relationship to the study drug drug the to study a causal relationship but
, 2 ( over timeover 9.0 0.05
the were reported deaths were No ) ≤
% . ( P
: 1C ● 3.0% only )
blind phase The incidence ofThe incidence hypoglycemic - 0.01 0.01 group comparison
MedDRA/J ver. were observed in 1 subject of the placebo group ( of placebo group in the 1 subject observed were
-
and 3 subjects of the Sitagliptin 50 mg theSitagliptin of and 3 subjects ), hypertension ≤ ),
).
2.9% )
; N P (
, P/S group Change in HbA % Within
●●: .
1 Name of adverse event the double poglycaemia
ubjects s Figure Laryngopharyngitis increasedWeight Hy Cystitis Gastritis Hyperglycaemia Hypoaesthesia Nasopharyngitis Upper respiratory tractinflammation Gastroenteritis Hypertension in Incidence Incidence l infarction
in the Sitagliptin 50 mg group and a causal relationship to the study drug was denied denied was drug study the to relationship a causal and group mg 50 Sitagliptin ) in the 2 ( Laboratory adverse events reported by at least 2 least at by reported events adverse Laboratory at least 2 subjects in either group were as shown in in as shown were group ineither subjects 2 at least by reported events adverse Clinical ligament injury ligament in the placebo group and 57.6% group thein placebo afety
. .Clinical adverse events reported by at least 2 subjectsin either group
cerebra Treatment was discontinued in in discontinued was Treatment in the placebo group and cerebral infarction cerebral 22
subjects and and
66 Table
) subjects Change from baseline (% baseline from Change
) of
5 incidence of clinical adverse drug reactions was 7.4% was reactions drug adverse of clinical incidence 68 placebo group placebo group . for all cases ; stenosis ) abnormalities test laboratory respectively 22. Table ( . all cases ; stenosis The incidence of laboratory adverse events was 7.4% was events adverse laboratory of The incidence fracture
Regarding s
) subjects
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page75
, ; ) 2 1 ] (
) of term 2 (
) 1 subject increased including including 100% ) subjects subjects
long-
(
) The change change The both groups groups both rib fracture rib is the number of of number the is 68 .
66
and in the placebo in placebo the 100% ALT
( , ) of the
of and
1
) ) ) 133 [ ) ) ) ) ) ) ) ) )
for for 7 5 8 7 6 6 5 5 4 19 48 = serious 10 ( ( ( ( ( ( ( ( ( ( (
10
( (
n group were as shown shown were asgroup (
11
1.54 kg 1.54 5.3 3.8 6.0 5.3 4.5 4.5 3.8 3.8 3.0
7.5 14.3 36.1 ± Total
diarrhoea 15.2% , respectively , were subjects ) ( ) 0.44 Safety analysis population analysis Safety - nitriteurine present 2 66 (
= ) )
) ) ) ) ) ) ) ) ) ) and n 7
new serious adverse events were events adverse serious new ( 2 4 15 5 3 5 4 5 4 4 22 both were not were both ( in the S/S group and the incidence in the S/S incidence and the group
( ( ( ( ( ( ( ( ( ( ( and and was
) blood urine blood present ) ) ), 52 subjects 3.0 6.1 7.6 4.5 1.5 6.1 7.6 6.1 6.1 - 10.6 new serious adverse event in event adverse serious new 22.7 33.3 and group
SD ) 1
S/S ± 133 Eight serious adverse events ( events adverse serious Eight pneumothorax traumatic pneumothorax
) subjects subject subjects and ) of
Laboratory adverse events with an incidence incidence an with events adverse Laboratory 1 ), subjects of which 4 which of . 67 4
67 66 s (
mean mean =
) of subjects] ( ) ) ) ) ) ) ) ) ) ) ) n 6
( of of subjectsin either group 4 5 1 3 3 4 5 2 0 1 0 2 events of gastrointestinal of gastrointestinal events adverse of incidence The
of in the placebo group group placebo the in 133 1 the incidence of clinical adverse events was 80.6% was events adverse of clinical incidence the
( ( ( ( ( ( ( ( ( ( ( ( *
( . 66 12 % 75
. group Treatment Weeks 12 3 )
60 ( 3.0% 6.0 7.5 1.5 4.5 4.5 6.0 7.5 3.0 0.0 1.5 0.0 of
( but a causal relationship to the study drug was denied denied was drug study the to relationship causal a but ( 3 subjects ( subjects 3 38.8 of
group d , subjects 1.5% 1 17 in [ ( an
P/S 7
100% 50 mg ) ) (
52
was
90.9% theof P/S group
) ) 9.0 to adverse events and adverse drug reactions drug adverse and events adverse
12.8% ( increased incidence subjects diarrhoea
(
) d. reporte were deaths No occurred in in occurred , group S/S the of 133 diarrhoea
, phase treatment term ) , of
MedDRA/J ver. eczema
ine to Treatment Week Week toTreatment ine , ) week treatment with Sitagliptin with treatment week
increased increased - in the Sitagliptin Sitagliptin in the
N
35 (
(
the P/S group and group P/S the %
CK enteritis infectious enteritis % ). subjects the- long Name of adverse event vomiting including in
(
) in 1.39 kg
.Clinical adverse events reported by at least 5 changes as judged by the investigator. the by judged as changes Treatment Weeks 12 Weeks Treatment and
26.3
Data from 40 133 were 23
; ± Headache Hypertension Nasopharyngitis Upper respiratory tractinflammation increasedWeight Osteoarthritis Periodontitis Hypoaesthesia Gastritis Rash Joint sprain Contusion Incidence Incidence *
and laboratory adverse drug reactions reported by at least at by reported reactions drug adverse laboratory and Clinical adverse events reported by at least 5% of subjects ineither subjects of 5% at least by reported events adverse Clinical
incidences of laboratory incidences afety . of , nausea ) . 5% ( Table were were white blood cells urine positive urine cells blood white in the Sitagliptin group group Sitagliptin the in subjects
2 ( 23 ), 67
) subject overall overall 1.5% of 1
bjects The denominator is the number of cases with pretreatment and posttreatment laboratory data available and the numerator the and available data laboratory posttreatment and pretreatment with cases of number the is denominator The cases with abnormal with cases
54 hepatic neoplasm malignant neoplasm hepatic 1.5% of clinical adverse drug reactions was 4.5% was reactions drug adverse of clinical ( in Table in 11 The Regarding s symptoms symptoms in severity mild were group Sitagliptin in the cases
respectively combined and basel from weight in body treatment was not associated with associated not was treatment su group and 0.40 group ( of at least ( ) abnormalities test laboratory during detected patella fracture patella of
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page76
.
4 1C ( of **
(no and 133 s
20 blind blind - 50 mg glycemic of HbA
subjects subjects study study 1 ***
). ( 2 [ in kg 2.06
label phase, label phase, 1 subject in 147 - 08 - throughout the the throughout blind phase phase blind n 50 mg during during n 50 mg
0.8% - 4 weeks and on another another on and weeks 4
body weight from from body weight ≥
, 65 ofof cases 65 130, all all 5435 week, randomized, randomized, week,
- - excluding of which and incidence and the 1 subject]; 140 mg/dL ator after mg/dL 140
ere week open week
- w ONO )
hepatic neoplasm malignant neoplasm hepatic ) group (
st abnormalities) leading to abnormalities) st ) subjects , in group the placebo 72 subjects arget number number arget The change in change The t at a stable dosage for dosage a stable at ( .
in combination with metformin combination in 50 mg 133 diarrhoea subjects treated with placebo during with treated subjects placebo during 12
once daily before breakfast. If If breakfast. before daily once ,
in the P/S and 0.76 ± group of phase and a 40 and phase 68 10 weeks and not on any other oral antihyper oral other any on not and weeks 10
lack of efficacy [ of efficacy , lack (
, analysis the safety 4 was classified as an adverse drug reaction drug an adverse as classified was
≥ cts were discontinued from the from discontinued were cts
in 3 subjects ( metformin
in 52 1.91 kg vomiting to ,
9.0% on 9.0% , the dose of Sitagliptin was to be increased from from be increased , the to was dose of Sitagliptin
subjects
≤
3 subjects] administered 12 76 comparative Five subje , Study Number , Study 5.3.5.1.6 lem treated subjects ( subjects 149 treated 1.24 ± blind phase (12 weeks) and Sitaglipti and (12 weeks) phase blind ( Subjects were to continue metformin 145 weeks prior to the start of the double the of start the to prior weeks -
. metformin, consisting of a 12 consisting metformin, nausea . , of which rash which of ( 2
1 6.0% and and 6.0% orally
at a stabledosage for
were included were included ) was ) within the previous 8 weeks 8 previous the within )
. ≥ ≥ group, group, - 1C Sitagliptin and the in group the placebo each (1 subject ) weeks SD subjects treated with Sitagliptin 50 mg during the during double with 50 mg Sitagliptin treated subjects , group subjects in the Sitagliptin Sitagliptin in the subjects
to be ± 52 77 ) group 76 for efficacy for metformin
( S/S ,
pioglitazone adverse events was 3.0% was events adverse Weeks Treatment
mean mean FAS 50 mg ofthe ombination study group]
), all of12 weeks the c blind, parallel blind, ) -
( (excluding (excluding
(including laboratory te laboratory (including events adverse ew during of Sitagliptin with Sitagliptin of
P/S oglycemic dose were permitted) dose 6.5% and 10.0% < on hree n
study study etformin Sitagliptin Sitagliptin of safety and efficacy the evaluate to ≥ T
occurred ) 1C
blind phase M
. glycemic agent glycemic , deteriorated glycemic control found on the start day of treatment of day start on the found control glycemic 50, deteriorated mg group - ≥ was glucose blood fasting or 24 Week atTreatment or after ) phase treatment term taken at at taken as dose the same at ) .3 blind [ phase metformin - ng- and all of these events were mild or moderate in severity in moderate or mild were events these of all and **] label phase (40 weeks) were were weeks) (40 phase label ; rash; and sciatica ; rash; term therapy. combination of the safety
events controlled, double ] - .(3) were included in the included were 7.0% 7.0% . group al antihyper al
, group the in placebo ubjects ≥
ges in in ges s s within the previous 8 weeks or patients with HbA with patients or weeks 8 previous the within s long subjects in the Sitagliptin Sitagliptin the in subjects
Patients with HbA
relisted 71 cases per group cases single or was was subjects in the placebo group, consent withdrawal [ consent withdrawal group, the in placebo subjects Sitagliptin the 12
to *** 20 combination A 4.(iii).A all for discontinuation discontinuation - theopen the the during double mg 50 Sitagliptin or Placebo agent with no data after the start of the study the of start the after data no with group) For the lo placebo- was conducted in Japanese patients with type 2 diabetes mellitus diabetes 2 with patients type Japanese in conducted was Treatment Week 16 and there was no safety prob 16 and there no safety was Week Treatment visit scheduled next at the to 100 mg 50 mg the double [ The incidence of hyp of The incidence period study ( symptoms gastrointestinal of events adverse For the double chan 77 ) subjects baseline to Treatment Week 52 ( Week Treatment to baseline the S/S
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page77
2
10 by ) is P/S and
)
group ) .001 igure consent
0
%
F test value
] , ( - - LOCF < as factors as factors )
t
( P ).
as as a covariate 0
P bind phase 100 mg ; Treatment ; Treatment 0.23 - CI
- 1C
12
adverse events adverse ) 95% status 0.56, 0.14, 0.46] Treatment Week Week Treatment
- [ ( [
moving out of the out of the moving subjects in the < 7.0% was 39.8% < 7.0% 39.8% was a paired a paired
3 subjects] , FAS , S/S group (
68 1C ] [ P/S group P/S ( group, group,
Treatment Week Treatment Week
value at 12 weeks after after weeks at 12 value (
] 0.001 1C
<
(LOCF) subjects]
0.51 CI
an HbA - blind phase for the the for
P group included 76 double 76 included group 6 -
(
treatment data in the S/S in data treatment 95% as factors andbaseline HbA
0.88,
- [ subjects in the in the subjects 144 subjects
0.39 0.30 - status squares mean ficacy [ ficacy ) - achieving Change from baseline
the double Least subjects in the S/S in subjects of which , 13 inboth groups 52).
from baseline to Treatment Week Week to Treatment baseline from lack of ef lack , 12
Among the subjects who had their dose increased increased their dose the subjects had who Among 1C
e to Treatment Week 12 Week e to Treatment
Treatment Week 12 Week Treatment
) ) ept metformin for ( in the P/S and S/S groups are presented in in presented the are P/S and S/S groups 77
three subjects were discontinued from the study ( the study from discontinued were subjects three 52. ts with an even lower HbA lower an even ts with - (exc 0.85 1.21 HbA
( ( The dose of Sitagliptin was increased to increased was of Sitagliptin The dose
observed 0.69 -
subjects]; ) squares mean ). - subjects] difference group had a significant reduction compared to the placebo to placebo the compared reduction had a significant group 7.15 8.06 4 ere 4 including laboratory test abnormalities test laboratory including [ w ) (% ) from baselinfrom Treatment Week Treatment Week
Least Twenty
] Treatment Week Week Treatment C . SD ( blind phase completers, 77 subjectsin the S/S subjects in P/S, 48 the group subjects 1
( excluding 1 subject with no on- subject 1 with excluding -
50 mg
0 subjects]
49 ( ) )
2 Mean rawal
Week Week
0.85 0.94 ) group ( (
for efficacy for from baseline baseline from
7.72 7.93 until Treatment Week Week Treatment until S/S
) to Treatment Week 52 Week )toTreatment
lack of efficacy [ of efficacy lack subjects s [ events adverse , baseline from time over group were double were group
, Treatment Change in HbA
the Sitagliptin the
alyses were performed separately for separately performed were alyses FAS 97 1C endpoint of the change in change of the endpoint were included in the safety in analysis the included safety were ). as a covariate 24.
blind phase withd phase blind
in - ANCOVA including treatment group and prior antidiabetic agent antidiabetic and prior group treatment including ANCOVA group 13 N
76 71 and 1C other reasons [ reasons other ) Placebo phase treatment term
HbA /S , - comparison
24
subjects] P Table
g 3 to 100 mg, the proportion of subjec the of proportion to 100 mg, 0.001,
group] subjects in subjects the
< 50 mg vs. 50 m
treatment subject] for the group S/S
P 76
S/S ( eight subjects in the P/S the in subjects eight 0 1 - 50 mg
Treatment group 7 of 93 subjects, including 16 of 45 subjects in the P/S group and 21 of 48 subjects in subjects the and 21 of S/S 16 of P/S 48 group 45 subjects in the including 7 of 93 subjects, Sixty Sitagliptin Placebo Sitagliptin Between completers and 1 double 1 and completers efficacy efficacy primary he
including laboratory test abnormalities test laboratory including ANCOVA including treatment group and prior antidiabetic agent antidiabetic prior and group treatment including ANCOVA subjects in subjects the [ withdrawal and baseline HbA and baseline , group were included in the wereincluded (3 group). 13 The changes in The changes T
[ phase Week Week group shown in Table inshown Table their dose increase was 66.7% (62 of 93 subjects, including in 33 and (62 45 the 29 including oftheir66.7% P/S group 93 subjects, of was dose subjects increase of subjects proportion and the group) theof in S/S 48 subjects [ and significant reduction andsignificant Efficacy and safety an safety and Efficacy the effect was maintained was the effect from area [ 12) and the long Treatment Week 40 Week Treatment
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page78
. , , ± ) ) of 76 No and . 27 of There group group group in the ( 0.29
. - 7 Noneof ( subjects subjects
group group ). was None of the ofNone the 77 77 mg 50
) were reported reported were The incidence Theincidence placebo placebo each 9.2% 2 subjects ).
. of of ) ) subjects
in the P/S group ]
SD upper respiratory respiratory upper mg 50 ≥ 4 1 )
) the ( ( ±
77 SE in
± ed as an adverse drug drug adverse as an ed
of subjects subjects in the S/S group and the and the group in S/S the 5.2% 1.3% 1 mean mean 2 ) subjects ( (
77
), subjects 76 subjects ) (Mean Sitagliptin Sitagliptin and and leading to discontinuation to leading 68
12 of of ) )
77 . group ) of 1.3% 2 2 [ ( of 7
subjects
Durationtreatment of (weeks) ( ) of the ofthe 2 Laboratory adverse events reported reported events adverse Laboratory imputation (
77 . 50 mg ) in the Sitagliptin 50 mg and thegroup mg 50 thein Sitagliptin subjects subjects 2.6% the incidence of clinical adverse events events adverse clinical of incidence the of ( 2.6%
, LOCF ( ) 68 72 in the placebo group and group placebo the in
63 2.6%
( ( ks )
of clinical adverse events was 37.5% was events adverse of clinical
of of and 1 subject of the Sitagliptin Sitagliptin of the subject 1 and
) group occurred in ≥ in occurred group 3 5 without without The incidence of gastrointestinal symptoms symptoms gastrointestinal of incidence The
( ( wee
and more commonly than in than commonly and more ) ( eczema , respectively ,
increased
) 77 subjects 52 )
subjects FAS ( 78
of at least 2 subjects subjects 2 atleast arthralgia
GTP in the Sitagliptin Sitagliptin in the including laboratory test laboratory abnormalities including group group 72 , and neumonia in 28 p ( the incidence
( of subjects were
, in the placebo group and group thein placebo over timeover 5 ) ( , and γ % 76
1.28 kg (
1C ) subjects of in either . group group group
4 6.9% ( 77
) subjects blind phase increased of
in the P/S group and 81.8% group in P/S the - 72 including laboratory abnormalities test laboratory including term treatment phase ( phase treatment term Sitagliptin 50 mg 3 5.3% placebo -
(
reported
of Change in HbA ) . 2 and but a causal relationship to the study drug was denied for both cases both for denied was drug study the to relationship a causal but 2 ( ) Serious adverse events ( events adverse Serious
), subjects) blood TG blood . 3.9% the double the long , (
Figure
68 in in was not not was 2.8% Durationtreatment of (weeks) of subjects
Clinical adverse events reported reported events adverse Clinical The incidence of laboratory adverse events was 10.3% was events adverse of laboratory incidence The in the placebo group and 36.4% group thein placebo 49 was was afety afety . . ( 72
pneumonia increased )
aemia in the Sitagliptin 50 mg group and the incidence of laboratory adverse drug reactions was reactions was drug adverse laboratory of incidence and the group 50 mg in Sitagliptin the The change in body weight from baseline to Treatment Week Treatment to baseline from weight body in change The % of . ± and 0.42 in group the placebo were reported were 3 ( ALT
72.1
) subjects Change from baseline (% baseline from Change
) ypoglyc diarrhoea clinical adverse drug reactions in the Sitagliptin 50 mg the Sitagliptin in reactions drug adverse clinical was events adverse of laboratory tract inflammation tract incidence of clinical adverse drug reactions was 4.4% was reactions drug adverse of clinical incidence ) subjects 4.2% (1 event) group subject1 placebo the by of ( (1 event) 72 6.9% was reactions drug adverse of clinical incidence ( events adverse no were Sitagliptin 50 mg group and the 1 case in the placebo group only was classifi was only group and the ingroup placebo 1 case the 50 mg Sitagliptin reaction was deaths deaths H ( the laboratory adverse drug reactions in the Sitagliptin 50 mg group occurred group 50 mg Sitagliptin the in reactions drug adverse laboratory the more commonly than in the commonly more Regarding s Regarding s tively respec
tively respec 1.24 kg were in at least 2 subjects of subjects 2 in the least at
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page79
. , ; the aortic and nausea prostate , subjects a causal a causal including including ; 9
( ] and chest pain chest
for for
) in 2 subjects
**
subjects of the ) 52 and all of these andall of these ) ) ) ) ) ) ) ) ) 145 were were
4 ) subjects
6 9 9 8 7 5 6 8 6 40 group relisted ( ( ( ( ( ( ( ( ( (
=
[ to
n . group
in 52 (
4.2 6.3 6.2 5.6 4.8 3.4 4.1 5.5 4.1 ) subjects 27.6 145 12 P/S to ) occurred in
Total of
145 1 diarrhoea events Adverse events events adverse serious new ( )
** . of
% 77 for for
4 )
= (
) ) ) ) ) ) ) ) )
n 6 6 5 5 4 4 21 4 5 5 ( ( ( ( ( ( ( ( ( ( (
, but of S/S group the
aortic dissection aortic 7.9 7.9 6.5 6.6 5.2 5.2 5.2 6.5 6.5 did not resolve even after treatment treatment after even resolve not did
27.3 )
kg in the S/S 2.11 ; 2.8% group
52 er grouper - in total in group and 7 and group
) subjects
Weeks Treatment respectively S/S
) 3 subjects 3 subjects the of 44 , were classified as adverse drug reactions drug adverse as classified were (including laboratory test test laboratory (including events Adverse
was
P/S 0.48 ± Treatment Weeks 12 Weeks Treatment ) .
but its causal relationship to the study drug drug study the to relationship its causal but - 145 in , 68
) increased creatinine blood
= of )
) ) ) ) ) ) ) ) ) n ring ( 0 3 4 3 3 1 2 3 1 19
6
( ( ( ( ( ( ( ( ( ( *
of the ( ) subjects
and )
of subjects in eith in subjects of 79 increased
0.0 4.4 5.9 4.4 4.4 1.5 2.9 4.4 1.5 adverse events was 0.7 was events adverse
symptoms 27.9
76 group Treatment Weeks 12 5% (
detected during detected 4.1% P/S of ALT 6 Safety analysis population analysis Safety ( in the S/S group and n = 1 = n and group S/S the in The change in body weight from baseline to Treatment Week Week Treatment to baseline from weight body in The change (
ALT increased ALT and
(relisted); (relisted);
including laboratory test abnormalities test laboratory including .
were and
, aortic dissection aortic blood creatinine increased creatinine blood , ( n = 76 and ) haemorrhage ulcer duodenal
, 7.9%
ver.9.0 . Adverse events (including laboratory adverse events) events) adverse laboratory (including events Adverse . ) hypoglycemic rash and r ); reported by at least /J , 25 ) gastrointestinal gastrointestinal group and in the S/S group and the incidence of laboratory adverse drug reactions reactions drug adverse laboratory of incidence the and group the S/S in and vomiting
loss loss of consciousness )
of )
Table
group and P/S group 1.86 kg in the S/S reported by at least 5% of subjects in either group were as shown in Table Table in shown as were group either in subjects of 5% least at by reported colon cancer colon for ash papula
colon cancer colon stenosis; spinal lumbar ; r
MedDRA
; and
)
), week treatment with Sitagliptin with treatment week ; - ] N chest pain ( lower limb lower 0.23 ±
lower limb lower subjects increased , (
subjects
( - %
Name of adverse event TG including increased 76
( increased 68
subjects The incidence of
of detected du detected to discontinuation leading ) was iarrhoea retinopathy iabetic asopharyngitis ash pneumonia czema
GTP of For laboratory adverse events ( Data from 40 Blood D R D N γ Upper respiratory tractinflammation ALT E Back pain angina pectoris angina
Incidence Incidence * ** 15 145 3 nts eve adverse serious new Of which ( SD 200 mg/day 200 ( Ten serious adverse events ( events adverse serious . Ten (relisted); rash (relisted);
[
± of and 1 ; (
4.4% . group
19.7% mean mean
weakness uscular overdose overdose M . discontinuation S/S dissection events ofincidence adverse was was ) events adverse laboratory 25. weakness muscular relationship to the study drug was denied for all events for denied was drug to study the relationship abnormalities) was denied was in 6 subjects of which 2 ( cancer One death occurred in the the in occurred death One and 0.7% in severity in moderate or mild were events 52 (
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page80
8 1C ( 65 **
(no P/S and
were 20 blind blind
group - during glycemic HbA
130, subjects subjects *** [
15
label phase, label phase, group) 134 -
by Treatment Treatment by 09
subjects in the in the subjects subjects inthe throughout the the throughout blind phase phase blind 4 weeks and on other other on and weeks 4 lack of efficacy efficacy of lack glimepiride blind phase phase blind
- - 2 Treatment Week Week Treatment 7 , ≥
( (
subjects in the
- 5435 50 mg for for week, randomized, randomized, week, ). - - excluding 4 subjects 4 subjects excluding subjects]; 60 of which 100 mg ( 140 mg/dL ator after mg/dL 140
7 during theduring double week open week
- subject] ONO group
subjects]; 1 glimepiride ) group 2 S/S blind phase 50 mg treatment data in the S/S in data treatment , in group the placebo 67 subjects inue atastable dosage arget number of cases of cases of number arget
t group included 69 double 69 included group (
130 subjects
50 mg the area [ thearea in combination with in combination subjects treated with with placebo treated subjects 14
once daily before breakfast. If If breakfast. before daily once
phase and a 40 and phase 60 10 weeks and not on any other oral antihyper oral other any on not and weeks 10 lack of efficacy [ efficacy of lack
(
,
≥ glimepiride
, consisting of a12 of consisting , of which ). subjects inthe 61 subjects 9.0% on ,
subject] , the dose of Sitagliptin was to be increased from from be increased , the to was dose of Sitagliptin subjects
≤
1 moving out of moving administered ind phase (12 weeks) and Sitagliptin 50 mg during during 50 mg Sitagliptin and (12 weeks) phase ind abetes mellitus abetes 80 , Study Number , Study 5.3.5.1.7 , comparative three subjects were discontinued from the study the from discontinued were three subjects (
clinical adverse events [ events adverse clinical and ( subjects 138 treated
bl - 131 - , Subjects were tocont were Subjects . glimepiride , .
2 subjects] 6.5% 12 weeks prior to the start of the double the of start the to prior weeks 12
orally at a stable dosage for .
≥ , analysis the safety in included were P/S group
≥ group, group, 1C - Twenty subjects] with ) weeks . gliptin gliptin Sita with treated subjects subjects in the Sitagliptin Sitagliptin in the subjects ) within the previous 8 weeks weeks 8 previous the within ) subjects] 3 to be The dose of Sitagliptin was increased to increased was Sitagliptin of dose ). The excluding 1 subject with no on- 1 subject with excluding
5 52 71 ) group 70 glimepiride
( ,
Nine subjects were discontinued from the study the from discontinued were subjects Nine blind phase completers, 71 subjects in the S/Sthe in subjects 71 completers, phase blind taken at at taken - .
as subject] ) group pioglitazone
ombination study study ombination
50 mg 1 c group] ), all of 12 weeks the subjects in the subjects clinical adverse event [ event adverse clinical for efficacy for
blind, parallel blind, combination therapy combination -
( <10.0% on a S/S
- double the for separately performed ses were 49 thein Sitagliptin 1 subject group, placebo the in subjects of Sitagliptin Sitagliptin of P/S ( [ 3
dose were permitted) dose ( for efficacy for s (excluding were included in the safety analysis, in the analysis, included safety were
group were double blind phase withdrawals phase blind
- , group 7.0% and 15
) ≥ , consent withdrawal [ , consent withdrawal group to evaluate the efficacy and safety of Sitagliptin of safety and efficacy the toevaluate
limepiride FAS 1C ) subjects in the FAS blind phase G
- other reasons [ ≥ was glucose blood fasting or 24 Week atTreatment or after phase treatment term ) dose the same at ) , 110 .4 blind phase group] glimepiride 50 mg , consent withdrawal [ withdrawal consent , group
subjects in subjects the - glycemic agent glycemic
**] label phase (40 weeks) were were weeks) (40 phase label term of the safety controlled, double - .(3) 7.0% 7.0% 70 S/S S/S [
tihyper ≥ , group the in placebo subjects s within the previous 8 weeks or patients with HbA with patients or weeks 8 previous the within s long subjects in the Sitagliptin Sitagliptin the in subjects Sixty subjects in the P/S the in subjects Sixty Patients with HbA with Patients completers and 2 double 2 and completers
64 10 subjects] placebo group, consent withdrawal [ withdrawal consent placebo group, the Placebo or Sitagliptin 50 mg during the during double mg 50 Sitagliptin or Placebo - theopen data efficacy no with inthe oral an oral was was period study ( the in included the double phase 15 14 placebo- - long For the
was conducted in Japanese patients with type 2 di 2 with patients type Japanese in conducted was , group
A combination study study combination A 4.(iii).A to*** 20 were included were included Efficacy and safety analy safety and Efficacy subjects in the P/Sthe in subjects cases per group per cases changes in in changes For the double Sitagliptin Sitagliptin [ agent Treatment Week 16 and there was no safety problem 16 and there no safety was Week Treatment at to the 100 visit next mg 50 mg scheduled 71 Week 40 in Week
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page81
3
of as 27 60 ) as a ) is ( and
%
( 1C
) 34 of
) (
0
] .001
Figure status test 0
- LOCF
value 0.29 t CI ( - 24.8%
- <
P P
dueto lack of 95%
0.11, 0.47] 0.65, was was - [ )
[
) a paired a paired Treatment Week Treatment Week FAS ( , SE (
). group in S/S the
7.0% ± <
are presented in presented are ] 0.001 1C as factors and baseline HbA baseline and factors as
< ) (Mean (LOCF) 0.55 CI
subjects
-
, Treatment for the, Treatment group P/S P
( HbA status in the P/S group and 33 group thein P/S ) 95% squares - 0.98, 0.47 value at 12 weeks after their dose dose their after weeks at 12 value 0.29 - - Durationtreatment of (weeks) mean an
[
imputation Change from baseline 1C
Least subjects glimepiride
LOCF
49 12
) ) 52). inboth groups ept for of without without ( from baseline to Treatment Week 12 Week to Treatment baseline from ) 0.87 0.80 ( ( (exc
30 The percentage of The discontinuations percentage
1C
e to Treatment Week 12 Week e to Treatment
) FAS group had a significant reduction compared to the to the compared reduction had a significant group (Treatment Week 12 Week (Treatment in the P/S and S/S groups S/S groups and P/S the in ( 81
7.54 8.13 52. % ( ) observed Treatment Week
the incidence of clinical adverse events was 50.7% was events adverse of clinical the incidence mong the subjects who had their dose increased from 50 from increased their dose had the who subjects mong SD 0.76
in the P/S group and 13 ofgroup 60 in P/S the ( -
,
50 mg over timeover ere A
including including 0 )
). w from baselinfrom %
) ) ( Treatment Week Week Treatment
Mean C squares mean difference ( - 1 1C 0.73 0.79 ( (
subjects Least , subjects 8.14 7.90 ). subjects blind phase - Treatment Week Treatment Week 109 130 prior antidiabetic agent and prior antidiabetic group treatment including ANCOVA as a covariate and the proportion of subjects achieving of subjects and the proportion from baseline baseline from
until Treatment Week Week Treatment until
) to Treatment Week 52 Week )to Treatment
d the Sitagliptin Sitagliptin the d . Change in HbA of 1C of s N over time from baseline baseline from time over 70 3 64 Change in HbA
an 63 1C endpoint of the change in HbA in change of the endpoint 17 ( Placebo ( 26. 0.001, HbA
the double
26
Figure
<
phase treatment term g Durationtreatment of (weeks) HbA including 14 of 49 including - P
S/S group S/S the proportion of subjects with an even lower HbA lower even an with subjects of proportion the (
Table Table ,
13.1% 50 m 50 mg vs. treatment
was was ) in S/S group the for the
Treatment group , subjects 100 mg Sitagliptin Between Sitagliptin Placebo comparison
covariate ANCOVA including treatment group and prior antidiabetic agent antidiabetic prior and group treatment including ANCOVA to
Change from baseline (% (% baseline baseline from from Change Change ) )
bjects efficacy efficacy primary he su increase was 57.8% was increase Regarding safety in safety Regarding in changes The
T 12) and the long Week 0 Week presented in Table presented in Table placebo group of 109 factors and baseline andbaseline factors and significant reduction andsignificant efficacy the effect was maintained was effect the mg
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page82
, , , ) 2 )
% ) drug SD in the the in ± 73.3 50 mg ) placebo
just subjects ) subjects incidence vomiting in the P/S P/S the in
the mean mean 71 71 group and thegroup
of Adverse events events Adverse Serious adverse adverse Serious ) of ] subjects . 9 . 71 ( , nausea
. group
( =
71
13
) subjects n ( 50 mg in thein placebo group (
Safety analysis population analysis Safety of ) (
60
2 mg 50 inSitagliptin the 12.7% [ ) ) ) ) ) ) ) ) ) ) ) 50 mg
group
5 4 2 2 2 2 2 2 2 7 2
) ( ( ( ( ( ( ( ( ( ( ( of Laboratory adverse events events adverse Laboratory
% 18.3 mg .
and 7.0 5.6 2.8 2.8 2.8 2.8 2.8 2.8 2.8 9.9 2.8 group resolved with resolved group 11 symptoms , respectively , 50 ( ) ] subjects
) in the placebo group and 8.5% group ) in placebo the
blind phase) blind and - subjects of the placebo group ( group placebo the of subjects
% subjects in the S/S group and the the and S/Sgroup thein 67 2 diarrhoea ) d 1 subject of the Sitagliptin Sitagliptin the of subject 1 d 50 mg , ouble of 71 in the Sitagliptin D an ( Sitagliptin subjects
4 subjects subjects )
[ and more commonly thanin commonly and more of
) , respectively , were reported deaths were No 67 ) subjects 4 66 71 in the Sitagliptin Sitagliptin in the 67 (
subjects ).
of =
] subjects of and the incidence of laboratory adverse drug drug adverse laboratory of incidence the and
of 60 n gastrointestinal 4 ) ( group group
71
5 e incidence of laboratory adverse drug reactions reactions drug adverse laboratory of e incidence ( ) ) ) ) ) ) ) ) ) )
( 8 4 4 0 1 0 0 2 0 2 16 0 71
( ( ( ( ( ( ( ( ( ( ( ( of
of 5.6%
of
) 71 subjects
diarrhoea was was events adverse of clinical incidence the
) subjects
0.99 kg 0.99 of 6.0 6.0 0.0 1.5 0.0 0.0 3.0 0.0 3.0 0.0 , 82 subjects ± ] 23.9 11 of were reported reported by were 66 1 ( in the Sitagliptin Sitagliptin in the ( 71 [ was was
71 37 % 11.3 % % ( of
Placebo group of
case 3 8.3
3 ( subjects 93.0
and (
) group thein S/S 9.0 67 coronary artery stenosis artery coronary vomiting 52.1%
Sitagliptin 50 mg mg 50 Sitagliptin , ;
4.2% of
4.2% and the 1 ( 1 [
hypoglycaemia ), ) subjects and
, phase treatment term ) subjects
60 MedDRA/J ver.
, ) 71
N of (
increased increased of
vomiting
4 % ( (
) subjects Name of adverse event
in and the P/S group 17 and 0.50 bo group in place the % [1 of 71 subjects] CK ( ) in the Sitagliptin 50 mg and thgroup 50 mg in Sitagliptin the
66 events of adverse The incidence gastroenteritis izziness ( 7.5
Diabetic neuropathy Diabetic D Arteriosclerosis Nasopharyngitis Upper respiratory tractinflammation Hypoglycaemia retinopathy Diabetic Diarrhoea Periodontitis Electrocardiogram prolonged QT Back pain 6.7% Incidence Incidence of The incidence of laboratory adverse events was 18.3 was events adverse of laboratory incidence The Clinical adverse events reported by at least 2 subjects in either group were as shown in in as shown were group ineither subjects 2 at least by reported events adverse Clinical The incidence Theof incidence
in the placebo group and group thein placebo .Clinical adverse events reported by at least subjects 2 in either group blood blood 2 . . f clinical adverse drug reactions was 6.0% was reactions drug adverse f clinical nausea ( was was 1.06 kg 1.06 27
( e
subjects
± )
event) acute myocardial infarction acute myocardial ) abnormalities test laboratory including ( 2 cases were classified as adverse drug reactions, but did not lead to study drug drug study to lead not did but reactions, drug as adverse of classified whichwere cases 2 1 (
60 wer Table 3.0% 5.6% of ) subjects
) 6 of 71 subjects 44 respectively 27. Table was was diarrhoea and , group . discontinuation ( of the subjects 2 least at in reported incidence o incidence The incidence of laboratory adverse events was 7.6% was events adverse laboratory of The incidence 67 group group . interruption respectively events events events) ( group The change in body weight from baseline to Treatment Week 12 ( Week Treatment to baseline from weight in body change . The group 50 mg Sitagliptin % and 23.9 group reactions was was reactions was 0.03 was ( of clinical adverse drug reactions was 1 was reactions drug adverse of clinical - inlong the safety Regarding
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page83
, to for
and
New were were arget )
t
.
( )
within the
20** 52
16
) and all of and all of
to
) ) )
) 131 *** ) ) ) ) ) ) ) ) ) ) ) ) ) )
) subjects subjects [ 12 5 8 6 6 8 6 5 4 4 3 8 8 6 6 40 15 15 = 10 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (
(
insulinsecretagogue
n detected during during detected (
10 3.8 6.1 4.6 4.6 6.1 4.6 3.8 3.1 3.1 2.3 6.1 6.1 4.6 4.6 an 7.6 131 131 11.5 11.5 ( 30.5
glycemic agent glycemic vomiting vomiting Total of of
- 5435 ) for - 5
15 ( 71
(
diabetes mellitus diabetes = )
) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) n 8 8 ( 4 5 4 3 4 1 4 4 4 4 0 26 6 5 3 3 ( (
( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (
ONO of subjectsin either group
glycemic agent
which resolved after treatment treatment after resolved which 5.6 7.0 5.6 4.2 5.6 1.4 5.6 5.6 5.6 5.6 0.0 8.5 7.0 4.2 4.2 Treatment Weeks Weeks Treatment 11.3 11.3 36.6
. 2.07 kg in S/S group the group ) subjects
± S/S
131 )
oralantihyper
) of 60
)
= 52 2 )
- ) ) ) ( ) ) ) ) ) ) ) ) ) ) ) ) ) ) 4 n to discontinuation leading 7 7 7 (
1 5 4 3 2 2 1 0 0 3 2 3 3 3 1 ( ( (
( ( ( ( ( ( ( ( ( ( ( ( ( ( (
*
including laboratory test abnormalities test laboratory including % ( , Study Number , Study 1.7 8.3 6.7 5.0 3.3 3.3 1.7 0.0 0.0 5.0 3.3 5.0 5.0 5.0 who hadwho not received an oral antihyper 11.7 11.7 11.7
23.3 group 1.5
P/S 83 adverse events was 11.5% was events adverse 10.0%
and
< aseline to Treatment to Treatment baseline from weight in body The change
, ) 5.3.5.2.1 . ( % and% pyuria Safety analysis population analysis Safety % who % had received singlea ( nausea 6.5
but its causal relationship to the study drug was denied was drug study the to relationship causal its but and in 1 subject of the, of P/Sin group 1 subject 9.0
≥
≤ 1C
for for
hypoglycemic and 0.28 1.70 kg in group the P/S rash cystitis
HbA
% and% , group ver.9.0
6.0 /J
≥ were were S/S
0.36 ± ) subjects
1C events adverse serious Two ious weeks 8 including (
. 52
HbA 131 MedDRA to term treatment study study treatment term ) was study in Japanese patients with type 2 type with patients Japanese in study treatment term
), week treatment with Sitagliptin (Treatment Weeks 12 Weeks (Treatment Sitagliptin with treatment week verse events of gastrointestinal symptoms was 3.8% was symptoms gastrointestinal of events verse -
- Name of adverse event -
of
N (
ad
3 SD
% increased ( The incidence of
. Adverse events (including laboratory adverse events) reported by at least 5% least at by reported events) adverse laboratory (including events Adverse .
± (including laboratory test abnormalities) test laboratory (including
Long
) within the prev the within ) 28
CK subjects and new serious adverse events detected during detected events adverse serious new and subjects )
increased
2 .5 . 2.3% Data from 40 Table
) mean mean Incidence Incidence * label, long , ] ( Diarrhoea Contusion retinopathy Diabetic Spinal osteoarthritis Hypoaesthesia ALT Vertigo neuropathy Diabetic Eczema Arteriosclerosis Urinary tract infection Upper respiratory tractinflammation Blood Constipation Back pain Dizziness Nasopharyngitis Hypoglycaemia 28 .(3) 8 weeks or those weeks8 or with
Patientsdiet on and exercise therapy with ported in ported GI, or a biguanide or GI,
- vertigo in 1 subject of the adverse events events adverse Treatment Weeks 12 Weeks Treatment α re of the incidence diarrhoea 16 4.(iii).A *** 20** open- An reported were deaths No shown as were group in either subjects of 5% at least by reported events) adverse laboratory (including inTable . discontinuation previous these events were mild or moderate in severity in moderate or mild were events these Week 52 Week
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page84
at 1C or
. of other , 43 HbA and the Week 4 Week
(
s safety] , the 52. ’ 50 mg ) If
subjects Weeks is presented is presented
subject] 112 study closure study 1
. weeks , subjects )
to 100 mg was 41.0% was SE subjects excluding 2 52
± % 177 175 of 50 mg subjects] 9 < 7.0 ) (Mean Treatment was discontinued discontinued was Treatment 12 . 1C 13 ( until Treatment Week Week Treatment until
different timepoints different of which HbA from baseline from toTreatment
imputation
1C in consideration of in the consideration subject LOCF for efficacy moving out of the area [ out of area the moving
, achieving blood glucose from baseline to Treatment Treatment to baseline from glucose blood in HbA s without without ) ( by Treatment Week 52 in Week 100 mg by Treatment
subjects] FAS ( 84
, analysis safety he value at 12 weeks after their dose increase was was increase dose their after at 12 weeks value clinical adverse events [ events adverse clinical prandial - 13 , e effect maintained was
1C . th after Treatment Week 12 and there was no no was there and 12 Week at or Treatment after 140 mg/dL over timeover
over time from baseline to baseline from time over ) ≥ and nistered once daily before breakfast for for breakfast before daily once nistered
increased to increased % 1C ( )
subjects] hour post 1C 7 test - once daily t
significant reduction significant , treatment was discontinued was treatment ,
) lack of efficacy [ efficacy of lack , and the proportion of subjects subjects of proportion and the Sitagliptin Change in HbA ) . was conducted to evaluate the safety and tolerability of Sitagliptin of Sitagliptin tolerability and safety the toevaluate conducted was
4 ) to admi be orally s increased eir dose increased from from increased dose their had the who subjects Among treatment data were included in FAS the included were data treatment ere consistent, ere the change inHbA , the change wa ). subjects] Figure a paired , a 0.001 % 78.5 was events adverse clinical of incidence the was was subjects 4
, < consent withdrawal [ withdrawal consent
, the dose of Sitagliptin was to be increased from 50 mg to 100 mg at the next at to the 50 next 100 mg mg to, the from be increased dose of was Sitagliptin P
. treated subjects were included in t in included were subjects treated
(
( 0.001 Change from baseline (% baseline from Change ) The dose of was Sitagliptin ). There w There < 50 mg ue to a suspected tumor toue a suspected ). P ( if the dose D 57 of 105 ( (
subjects 7.0% or fasting blood glucose was was glucose blood or fasting 7.0%
≥ 38
1 subject] in subjects with- subjects no on 100 mg 54.3% 105 subjects was was problem safety scheduled visit scheduled 177 the All of Regarding safety Regarding Concerning efficacy Concerning
of ofcases 150 number Sitagliptin There was a significant reduction in 2- in reduction significant a There was 52 Week and thereafter in Figure 4. in Figure the relevant site [ site the relevant proportion of subjects with an even lower HbA lower an even with subjects of proportion [ reasons [ reasons
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page85
, ; ; st of was The iron 3
were were large (
;
). ; ) colonic vertigo cerebral subjects
; 5%
vomiting back pain ;
18 ≥ ), and
subjects in
all relisted all , nausea The incidence of The of incidence ( 177 (
subjects ). cardiac failure cardiac
of
loss consciousness loss of 9
( occurred in 177
loss ofloss consciousness
(including laboratory te laboratory (including )
) acute
) . hypoaesthesia
neuroma of
subjects
) ) ) ) ) ) ) ) ) ) ) ) ) ) ) symptoms ; ; anaemia deficiency iron
) 6 myocardial infarction myocardial 5.1% adverse events was 1.7% was events adverse 15
( 1/5 2/2
( ; (
loss of consciousness of loss (
8/176 3/176 1/176 3/176 1/176 1/17 1/176 1/176 1/176 1/176 8/176 7/176 2/176 1/176
177 ( ( ( ( ( ( ( ( ( ( ( ( ( (
and )
of which of which 100 20.0 ; dehydration 4.5 1.7 0.6 1.7 0.6 0.6 0.6 0.6 0.6 0.6 4.5 4.0 1.1 0.6 of ),
; Sitagliptin group 8.5% ( 18
and the numerator (
colitis and the incidence of laboratory adverse drug adverse drug laboratory of incidence ) and the gastrointestinal gastrointestinal abdominal pain abdominal Safety analysis population analysis Safety hypoglycemic ; dehydration (
erebral infarction erebral ;
c ; % 10.2
act inflammation act
;
85
constipation ischaemic ischaemic
6.8% (12 of 177 subjects) ( 177 subjects) of (12 6.8% ; 0 The change in body weight from baseline to Treatment to baseline Treatment The in from change body weight ), . neuroma 9 but its causal relationship to the study drug denied was . the to study its relationship but causal
).
;
Clinical adverse events with an incidence of incidence an with events adverse Clinical
) ver. ),
acute myocardial infarction
The incidence of adverse events adverse of incidence The
ic gonadotropin increased .
27 of176 subjects subjects The incidence of The incidence
( increased
. subjects
Laboratory adverse events
including laboratory test abnormalities test laboratory including
relisted
optic ischaemic neuropathy ischaemic optic he number of cases with abnormal changes as judged by the the by judged as changes abnormal with cases of number he . ( ( Of which, consciousness of loss
MedDRA/J Name of adverse event 177 29 , upper respiratory tr increased ). subjects
). 177 % subjects]; of myocardial infarction myocardial tty acids increased tty bilirubin CK increased
increased of increased 2 Table and ;
cardiac failure cardiac [ 176 1 62 ( ( GTP
Blood creatinine increased Blood glucose decreased Free fa decreased Haematocrit Haemoglobin decreased Platelet count decreased decreased count cell blood Red White blood cell countincreased chorion human Urine Occult blood positive ALT γ AST Blood increased acid uric Blood Blood
subjects]; of optic ischaemic neuropathy ischaemic optic ) The denominator in parenthesis is the number of cases with pretreatment pretreatment with cases of number the is parenthesis in denominator The andposttreatment laboratory data available parentheses is t investigator Incidence Incidence
%
; 4 2 acute acute ( [ hepatitis C (
spinal compression fracture spinal compression ;
cardiac failure failure cardiac ; ), subjects 35.0%
(
leading to discontinuation was was to discontinuation leading adverse events of events of adverse the incidences and 177 ) acute acute were all 0.6 all were of
events adverse serious ; ) ; cataract 9 gastric cancer gastric (
) ts subjec
5.1% carcinoma intestine large 177 classified as adverse drug reactions drug as adverse classified diarrhoea deficiency anaemia deficiency laboratory adverse events were as shown in Table 29 Table in shown as were events adverse laboratory specific of incidences ; polyp infarction ( intestine carcinoma intestine infarction acute myocardial Nineteen Nineteen ( laboratory adverse events was 15.3% was events adverse laboratory nasopharyngitis abnormalities) classified as an adverse drug reaction drug adverse as an classified death One occurred was reactions drug adverse clinical of incidence reactions was 2.3% was reactions dizziness
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page86
. , ) ] A In ) 25
. and 130 B Gault
- other to be to be ≥ , ] consent included 1 subject 1 subject , , was were eligible if Phase was was
Cockcroft ( ) on stable insulin insulin stable on A
) was allowed was chronic renal
was initiated in 2 2 in initiated was 20** who had received who had received consecutive e on 2 consecutive stage disease stage renal
agent and The study excluding 1 subject 1 subject excluding *
. and Stratum 2) and Stratum or , before randomization before randomization oneal dialysis
controlled Phase B controlled Phase ** they had been been had they ) - 1 , according to glipizide SU
subjects in the placebo placebo inthe subjects ( or ), perit
or end-
of /min A 25 glipizide L
10% m
loss loss consciousness of ≤ [ /min
and Stratum Stratum L at baseline at baseline glaucoma
( completion of completion Phase and , Phase
tablets ( .
week, active week, to < 50 - adverse event before randomization before event adverse 30 m
6.5% ** sulfonylurea
30 mg
≥ subject] <
strata strata
insulin insulin ≥ 20 5- completed Phase A Phase completed 1C 1 2 CR subjects treated with placebo in Phase in Phase placebo with treated subjects CR * After the After
C C . label HbA ( ** - for to be orally administered placebo or Sitagliptin , respectively to with with and 1 subject who withdrew consent in the the in consent withdrew who subject and 1 preexisting Rescue therapy with with therapy Rescue 130 mg/dL.
. > )
orally administered placebo or Sitagliptin or placebo to administered be orally 86 were up to four four to up . ) 20**
of stage renaldisease (on hemodialysis or on -
were were adverse event [ event adverse due to an adverse event ( event adverse an to due due to a due if fasting blood glucose at the end of Phase A Phase of end the at glucose blood fasting if
6 or 8 weeks weeks 8 or 6 ( who had been on been had who /min from the study from *** )
,
added to be added
[ ] ≥ the tolerability and safety of Sitagliptin of safety and tolerability the L
an subjects medications] used concomitant prohibited subjects ( ), or end 2
was those
from the study from . moderate renal insufficiency ( controlled Phase A and the 42 A controlled Phase /min agentfor - L
2.14 kg. and fasting blood glucose to < 50 m to
with with In Phase B Phase In dose increase dose
30 m
. If fasting blood glucose exceeded the reference rang reference the exceeded blood glucose fasting . If discontinued ified by renal function into into function renal by ified < 30 10%
glycemic CR 0.24 ± and Day 63 and 48 Day oup on Day ≤ ≥ - C and
discontinued who cerebrovascular accident cerebrovascular
( were were CR subject died; and us mellit diabetes 2 type with in patients study blind peritoneal dialysis peritoneal
controlled comparative study in patients with renal insufficiency [Foreign [Foreign insufficiency renal with patients in study comparative controlled - ) - C 1 ( antihyper [ ) was week, placebo week, on
ratio to placebo or Sitagliptin or placebo to ratio 7.5%
1 wasnot given to
subjects in the Sitagliptin group who had who group in the Sitagliptin subjects
) group tablet of glipizide of tablet ≥ 2
oral
12-
SD
1C an increased dose of insulin or open dose or of insulin an increased ± . an ) to evaluate conducted was Placebo mg subjects]
HbA on ) agent as rescue therapy rescue as agent group Sitagliptin the ints
17 5- 3 1 subject in the 1 subject placebo group diabetes mellitus patients
subjects] .6 , 2 subjects were strat glipizide mean mean SU with with 3 ( glipizide , i.e. the , / , Study Number P028Number , Study 5.3.5.1.16 one .(3) ( clinical adverse event and 1 subject who withdrew consent withdrew who subject 1 and event adverse clinical Phase B Phase A st. Subjects in Stratum 2 inStratum Subjects st. breakfa before daily once subjec
,
six of the 58 a - 7 once daily before breakfast before daily once Adult type type Adult
placebo 4.(iii).A study]
Reference data Reference mg , measurements administered as rescue therapy rescue as administered [on hemodialysis or [on hemodialysis 50 mg mg/dL ( 2 periods Phase Phase : 1 in a randomized Subjects in Stratum Subjects in Stratum formula), severe renal insufficiency ( monotherapy monotherapy 17
A randomized, double randomized, A 52 Week they had not been not had they insulin or Fifty entered A Phase In and insufficiency subjects in the Sitagliptin gr
discontinued were group Sitagliptin with an adverse event adverse an with with with group excluding 1 subject 1 subject excluding group However, However, withdrawal [ withdrawal reasons [ reasons
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page87
. , , ; ; ; ) 3 1 [
; and was
were large
) acute acute up group group - 80.0%
in the the in transient coronary coronary )
and and pancreatic ects in the
pneumonia ; ;
; subject] hypertension subj , anaemia
1
;
prostate cancer ; supraventricular supraventricular 4 [ group and group o/glipizide , The incidence of
lost to follow . after the completion completion the after and ,
oss of consciousness of oss ) l loss of consciousness loss myocardial infarction myocardial ( ) hyperglycaemia ; carcinoma pancreatic serious adverse events events adverse serious ( [ metastases toliver metastases
hyperglycaemia staphylococcal infection staphylococcal
hydronephrosis subjects] . Of these serious adverse adverse serious these Of . /glipizide of and ) ; , and bacteraemia ) sepsis subject]
colon cancer colon
2 ( ; ; in the placebo/glipizide group
1 ; and metastases to liver metastases subject in the Sitagliptin Sitagliptin the in subject
; myocardial infarction myocardial 1
, subjects] thalamic infarction thalamic group
eumonia consent withdrawal [ withdrawal consent
, ] 2 pn Clinical adverse events reported by at at by reported events adverse . Clinical oma of; skin oma ) subjects subjects in the placeb inthe subjects and tachycardia supraventricular ( in the placebo the in
2 26 ) and death
rescue therapy were were therapy rescue of initiation the before
hypertensive , and hypertensive oedema pulmonary acute of ; adverse events [ events adverse In Phase A Phase In polytraumatism ( , gastroenteritis cerebrovascular accident cerebrovascular
cardiac failure cardiac . ; serious adverse events occurred in 10 subjects in10 occurred events adverse serious
22
; ( subjects
subjects
Phase B, B, Phase
ter and discontinued from the study and then died then and study the from and discontinued ter squamous cell carcinoma of skin carcinoma cell squamous 3 87
n the Sitagliptin group, 29 group, Sitagliptin the n group ; la , hypertension I 26
In moving out [ of the area moving congestive failure cardiac pneumonia cerebrovascular accident cerebrovascular , .
.
; ischaemia myocardial 84.6% ; The percentage of subjects who did not receive rescue rescue receive not did who subjects of percentage The ) inopathy ; of
adverse events [ events adverse ; ( .
arterial and venous thrombosis venous and arterial as ret 22 .
renal transplant renal ( ; and and
[ urinary tract infection tract urinary , and squamous cell carcin cell squamous
glipizide
/ ; subjects] subjects] [1 subject used prohibited concomitant medications concomitant prohibited used subject [1 subjects] 2 in 1 subject of the Sitagliptin group was classified as an adverse adverse as an classified was group Sitagliptin the of subject 1 in subject with a serious adverse event adverse a serious with subject /glipizide placebo the in subject renal failure chronic failure renal gastroenteritis weeks w weeks
, anaemia
4 group Sitagliptin the in and 1 subject ; 1 group Sitagliptin the in 1 subject events, verse
, 54 from the study from in the Sitagliptin group Sitagliptin the in ) subjects] fatal serious adverse events were all all documented were events adverse fatalserious The and B - ) hyperglycaemia
gliptin group 2 from the study from . bronchitis after the initiation of rescue therapy rescue of initiation the after ( , stenosis artery renal diabetic foot diabetic pancreatic carcinoma
prostate cancer prostate , and transient ischaemic attack ischaemic transient
, ; ac failure
weeks was 84.6% was weeks ; gastroduodenitis subjects n Phase ; congestive failure , and cardiac staphylococcal infection staphylococcal
; . I bacteraemia in the Sita the in ) cardi 65 death during hemodialysis during death other reasons [ reasons other In the placebo/glipizide group, 22 the group, placebo/glipizide In discontinued )
( ; ;
, . and 1 subject in the Sitagliptin group ( group the in Sitagliptin and 1 subject and ] of
discontinued consent withdrawal [ withdrawal consent
Due to serious ad toserious Due pericarditis other reasons [ from the study from oup developed 5 subjects in the placebo in subjects 5 , , 50 were were died mentioned serious adverse events in events adverse serious mentioned ( ,
ts in the Sitagliptin in ts the group Sitagliptin -
) gastroenteritis were
; ) urinary tract infection
sudden death sudden gastroenteritis ; ( subjec 76.9%
, site infection eriovenous graft
abdominal pain upper pain abdominal prostate cancer prostate 52 of65 subjects myocardial infarction myocardial Sitagliptin gr Sitagliptin definitely diagnosed with with diagnosed definitely The above carcinoma discontinued discontinued ( hypertension ( , onlyevents consciousness loss of . reaction drug A of Phase cellulitis A Phase during ischaemic attack ischaemic crisis Sitagliptin group Sitagliptin haemorrhage intestinal art acute myocardial infarction myocardial , and acute tachycardia and artery stenosis artery occurred in 17 subjects occurred assessed and deaths and non and deaths and assessed through events adverse clinical In the primary safety analysis, adverse events occurring events adverse analysis, safety the primary In B Phase In and ] bacteraemia myocardial infarction myocardial died , died] subjects ( 10 hyperglycaemia subject] therapy throughout 54 throughout therapy
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page88
0 ], of [
and The 6
[ ] and
). 0.0% ] in the the in ] ( subjects 9.2%
subjects 65
subjects ] and 26 of
*
of
4
26 . ] 1 of26 subjects [ * ],respectively
5
[
[
cts
gastroenteritis
of even when analysis was was analysis when even
subjects
) ) ) )
) ) )
) ) ) ) ) ), 3 8 ) ) ) ) ) ) ) 4 65 1 1 3 1 5 50 18 ( (
65 15 2 0
0 0 0 0 0 ( ( ( ( ( ( ( [ 3.8%
6.2%
( ( ( ( ( ( ( ( 26 =
** (
=
subje n 19.2% n 1.5 1.5 4.6 1.5 7.7 (
12.3 3.1 0.0 0.0 0.0 0.0 0.0 0.0 ( 4.6 of ( in the placebo/glipizide group group in the placebo/glipizide 76.9 27.7
23.1
65 3
[ Sitagliptin group
Sitagliptin group 15.4% of (
4 [ the entire study period
) subjects
11.5% the entire period study (
26
] and subjects 6.2% of
group
of rescue therapy diarrhoea ), nasopharyngitis
26 6
) ( ) ) ) )
) ) ) ) ) ) ) ) 8 ) ) ) ) ) ) n group Sitaglipti the in 26 0 0 0 0 0
0 0 5 (
26 2 0 0 2 0 1 22 10 ( ( ( ( ( ( (
after the start of study drug administration drug study of start the after (
of
( ( ( ( ( ( ( ( =
=
lipizide 88 n lipizide group lipizide were g n 0.0 0.0 0.0 0.0 0.0 0.0 0.0 ( initiation initiation 1 30.8 / g 7.7 0.0 3.8 0.0 7.7 0.0 (
19.2 / [ 84.6 38.5
] subjects Placebo ] and subjects Placebo , respectively , ] 3.8% had developed ( 65 upper respiratory inflammation respiratory upper 26
urinary tract infection tract urinary of ), ), of
6
ure that [
1
[
dizziness o o
throughout adverse throughout events Clinical .
reactions . Laboratory adverse events throughout adverse events . Laboratory
adverse events was 23.1% was events adverse
)
of65 subjects . group in Sitagliptin the 0 3.8% ),
) 1 ) subject who discontinued due to the use of prohibited concomitant medications for for medications concomitant prohibited of use the to due discontinued who subject N ( 4 3
( 3 N
dverse events occurringafter the
( [
, respectively ,
% ]
% ], respectively ], , events adverse of occurrence of trend inthe differences
Table
ious adverse events Table Table 6.2% subjects leading to discontinuation drug adverse Serious reactions leading to discontinuation Adverse events drug Adverse Serious adverse events drug adverse Serious reactions Adverse events leadingto discontinuation reactions drug Adverse leading to discontinuation Ser Excluding adverse events occurringafter theinitiation of rescue therapy Excluding1
Deaths Serious adverse events drug adverse Serious reactions Adverse events leadingto discontinuation reactions drug Adverse leading to discontinuation Serious adverse events leading to discontinuation drug adverse Serious t leading reactions discontinuation Adverse events reactions drug Adverse
Excluding a Incidence Incidence *
ubjects the treatmentcardiac of fail Incidence Incidence * ** subjects and s
] cough , and of 65 ) 65 65 3 of subjects in the Sitagliptin group Sitagliptin the in subjects of (
of of 4 5 [ 5% [
], respectively ], subjects performed including adverse events occurring after the initiation of rescue therapy rescue of initiation the after occurring events adverse including performed respectively There were no major There were incidence ofincidence hypoglycemic and 4.6% least placebo/glipizide group and 9.2% and group placebo/glipizide 65 of26 subjects 7.7% 6.2%
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page89
in 2) no e), ( the
100 100
blind blind or - or the orthe are 50- F or at an hasbeen
confidence confidence 4.(iii).B.
there there in Japan and blind phasblind ,
- fell above fell
ee “ 95% the improvement improvement the s [ Sitagliptin ( selectively inhibits inhibits selectively
) a comparative study. study. a comparative that like existing oral oral existing like that ic agent of be alone used
monotherapy secretion and inhibition and inhibition secretion
that
was conducted. was
with its its with
) may . especially, especially, seful for patients for seful with Based on its mode of action, action, of mode its on Based
, . efficacy efficacy for the phase III double III phase the for P054 glimepiride s group ing conclud , confidence interval confidence
, the efficacy of Sitagliptin in Sitagliptin of efficacy the ,
the , drug % 10) nical studies have evaluated the efficacy theefficacy evaluated have studies nical - prandial hyperglycemia etc. hyperglycemia prandial - voglibose The prevention of the inactivation of these these of inactivation the of The prevention metformin control control as a drug that as a drug stimulation of insulin stimulation eriority of Sitagliptin to vogliboseto Sitagliptin of eriority . 5435
, -
a
inf and GIP
as )
ONO 89 ( in combination with existing oral antihyperglycemic existing with combination in
. agents antihyperglycemic and 1 dependent - accepted the response, the response, accepted -
and , the non- , the blind comparative study ( study blindcomparative pioglitazone
from baseline to Treatment Week 12 (double Week baselineTreatment tofrom ) - (
50 mg/day 1C the lower limit of the 95 the of limit lower the (
there is no approved drug with the same mode mode with same the drug no approved there is where the case In 0.2% glucose PMDA as
- commonly used as an oral antihyperglycem oral an used as commonly , (
HbA
diabetes mellitus when used as an initial as an used when mellitus diabetes by PMDA and prandial hyperglycemia and is u is and hyperglycemia prandial in patients with type 2 diabetes mellitus diabetes 2 type with patients in in the improvement of glycemicimprovement the in control
-
) are expected to improve post improve to expected are
Safety”] term treatment study treatment term
has been has - the choice of voglibose of choice the )
. 3 ) type 2 ( ( resulting 28, 0.51] 0. voglibose [
a long P054
iii).B. in in combination with other oral other with combination in inferiority margin inferiority
and 39% the applicant to explain the clinical positioning of Sitagliptin of positioning clinical the explain to applicant the controlled, phase III, double III, controlled, phase 0. in monotherapy ) Efficacy - dependent prevents the inactivation of GLP inactivation the prevents Also 1 - ). until Treatment Week 52. Therefore Week Treatment until maintained was Outline of the review 2) Efficacy Clinical positioning 1) Clinical was
, hyperglycemia prandial
and .(2 .( .( considers as follows: as considers asked asked - 4 - insulin oglibose defined non- - post
Efficacy” and “4.( and Efficacy” . agents antihyperglycemic oral other with combination s of action mode different agents with DPP potentiates hormones gastrointestinal , secretion of glucagon cli Japanese and action of mode novel a has Sitagliptin Since a monotherapy as of Sitagliptin and safety be chosen can , Sitagliptin agents antihyperglycemic the difference between the Sitagliptin the between difference the 4.(iii).B 4.(iii).B of glucagon reduce secretion, insulin to increase expected thatis a drug as positioned is Sitagliptin post improve and release, non- or dose increased follows: as responded The applicant of action new mode a with agent antihyperglycemic oral an is Sitagliptin 4.(iii).B PMDA A v PMDA 4.(iii).B interval . confirmed primary endpoint of the change in endpoint of change the primary pre mg/day) demonstrated. has been monotherapy for group control the as chosen be should Japan,in placebo asof Sitagliptin action voglibosesince However, both Sitagliptin study ( study comparative particular problems with with problems particular
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page90
,
. nt he he
the ** in a
, the
0.61]
-
and value - 0.927 0.914 P for each 1.00,
Interaction - between t pioglitazone
[
group group ) 45 mg/day were45 mg/day . Therefore .
the changes from from changes the *
For fasting blood blood For fasting subgroup variable variable subgroup - ed with 45 mg/day 45 mg/day ed with FAS CI] 0.81%
). ( by
- as a covariate as 1C
difference 95% placebo placebo .
o gender or the of or dose o gender tment ] ] ] ] was - was Placebo group the
(LOCF) (LOCF) 0.5 0.5 0.5 0.6
- - - - −
, interaction between treatme between interaction
1.1, 1.1, 1.1, 1.1, - - - - [ [ [ [ group
the
showed no major differences in the the in no majorshowed differences 0.8 0.8 0.8 0.8 . demonstrated - - - - gender and the dose and the of gender patients treated with treated patients according t according , for all efficacy endpoints including including endpoints efficacy all , for
, squares mean differences between t between differences mean squares 50 mg - was was compared to the to compared squares mean difference [ blind phase) until Treatment Week 52 Week Treatment until - - as factors and baseline HbA baseline and as factors
was not significant was ) confidence interval confidence , subgroup variable, and trea However Least Sitagliptin the number of patients treat patients of number the
status .
group )
status
) pioglitazone
(double
here were slight differences between the subgroups subgroups the between differences slight were here
90 s for the least s for subjects in the Sitagliptin group in Sitagliptin the subjects pioglitazone because 2
, was conducted and for the primary endpoint of the change change the endpoint of primary the for and conducted was lacebo group was maintained maintained was Sitagliptin P blind phase
- from baseline to Treatment Week 12 Week Treatment to baseline from
the ofpioglitazone dose
1C
19 49 ) P055
/ / group/ N other antidiabetic agent
28 38 35/30 31/38 were performed according to according performed were an other antidiabetic agent in the blood glucose, t glucose, blood double
( an ).P055 the dose of pioglitazone of dose , the 50 mg P055 Study of analyses subgroup
as as a covariate
12 confidence interval confidence P055 1C
100 mg/day) - according to
gender prandial - tudy Change in HbA with with therapy combination 95% Sitagliptin (
( .
with with therapy combination 2 3 the
combination study ( study combination
those treated with 30 mg/day 30 with treated those 32), Table Table hour post subject in the placebo group
Efficacy in combination therapy with in pioglitazone combination ) Efficacy between the Sitagliptin and placebo groups in groups and placebo Sitagliptin the between differences mean squares Sitagliptin (50 Sitagliptin combination study ( study combination . 1
- 2 ( 45 mg from baseline to Treatment Week 12 Week Treatment to baseline from
).
+ a significant reduction reduction a significant
of Table Table
as factors andbaseline HbA 1C asked the applicant to discuss the efficacy by gender and by the dose of pioglitazone the dose by and gender by the efficacy todiscuss the applicant asked
subgroup analysis subgroup ( pioglitazone .(2
considers as follows: as considers
Males Females 15 mg 1C 30 mg pioglitazone HbA
Dose of Gender ANCOVA including treatment group, priorANCOVA
ANCOVA including treatment group andprior ANCOVA subgroup ** * interaction interaction combined with with combined small was glucose and 2- for the least Week toTreatment baseline were wide and wide were subgroup each for groups and placebo Sitagliptin HbA group and each variable and each group
efficacy of Sitagliptin efficacy PMDA in As described in the above, the in described theAs above, The 4.(iii).B For the follows: as responded The applicant S of analyses Subgroup pioglitazone PMDA pioglitazone Sitagliptin (50 mg/day) and placebo groups with and placebo groups its 95% (50Sitagliptin mg/day) showing efficacy efficacy of Sitagliptin of Sitagliptin efficacy
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page91
the the that .
, , 0.88, 0.98, ] , P055 - - ( [ [ 7)
- ) hasbeen asked the
4 s
” erefore erefore 0.69% 0.76% - -
determined . Th . Th
cysts and polyps) PMDA
was was ,
3) Safety ( cases included included The 10 cases
benign, malignant and and malignant benign, the difference between
. PMDA . uding , of
4.(iii).B. the development of malignant development the studies treatment term - of Sitagliptin
ee “
[s
ies blind phase) blind phase), the difference between between difference the blind phase), - - . the response accepted confidence interval confidence confidence interval was interval confidence neoplasms (incl neoplasms
and of hepatocellular adenoma hepatocellular and of was demonstrated until Treatment Week 52 Week Treatment until until Treatment Week 52 Week Treatment until
. demonstrated was therapy
s Japanese long Japanese , PMDA
4 .
was conducted and for the primary endpoint of the the endpointof primary the for and conducted was was conducted and for the primary endpoint of the the endpoint of primary the for and conducted was 91 metformin between monotherapy and combination therapy and and therapy and combination monotherapy between glimepiride 09)
08) - term treatment stud treatment term - - pioglitazone was maintained was was maintained maintained was
differ 5435 ) ) 5435
bo groups with its 95% with bo groups , Sitagliptin with combined tobe agents s a consistent trend in the development inthe trend s a consistent
cebo groups with its 95% with cebo groups may i ONO-
ONO- tumors etc. reported were examined in detail examined were reported etc. tumors e cysts and polyps) and cysts ( tumor development tumor
and place 100 mg/day 100 mg/day uding in Japanese long inJapanese - - )
indicated indicated by assessed be should 50 50 ( ( idence of hepatocellular carcinoma hepatocellular of idence
week oral carcinogenicity study (4.2.3.4.1.3) and (4.2.3.4.1.3) study oral carcinogenicity week , 10 cases of ntihyperglycemic from baseline to Treatment Week 12 (double 12 Week Treatment to baseline from from baseline to Treatment Week 12 (double 12 Week Treatment to baseline from 10) a
reported -
a significant reduction in the Sitagliptin group compared to the placebo group and the and group placebo the to compared group Sitagliptin the in reduction significant a a significant reduction in the Sitagliptin group compared to the placebo group and the and group placebo the to compared group Sitagliptin the in reduction significant a 50 mg/day
1C 1C ( combination study ( study combination
combination study study combination oral ) Risk of hypoglycaemia to ) Relationship Efficacy in combination therapy with in glimepiride combination ) Efficacy Efficacy in combination therapy with in metformin combination ) Efficacy Sitagliptin a 106- rat Sitagliptin 08 to 4 3 - .1 .2 ). ). of of 3) Safety
hasbeen other .(3) .( .(3) .(2 .(2 showing showing showing considers as follows: as considers considers as follows: as considers an increased inc increased an 5435 , , - explained that there are no major differences in the efficacy of the combination of the combination in efficacy the differences that are no major the there explained applicant metformin glimepiride
0.51] 0.55] (hereinafter referred to as “tumors etc.”) from etc.”) “tumors as to referred (hereinafter ONO follows: as responded The applicant and unspecified malignant benign, on data Based on pooled the Sitagliptin the eoplasms (incl neoplasms unspecified Since the risk of hypoglycaemia the risk Since - efficacy 4.(iii).B 4.(iii).B 4.(iii).B 4.(iii).B PMDA A A 4.(iii).B PMDA As dose ofthe or to gender according therapy observed in observed tumors r the whether discuss to applicant Since among - efficacy the Sitagliptin (50 mg/day) and pla (50 mg/day) the Sitagliptin change in HbA in change HbA in change the risk of hypoglycaemia efficacy of Sitagliptin combination therapy with with therapy combination Sitagliptin of efficacy efficacy of Sitagliptin combination therapy with therapy combination Sitagliptin of efficacy
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page92
; ) 2 ). ( The CK ( ciated
As the subjects physical he cause cause he 0.1, 1.3] an adverse adverse an - . T [ 10 , patients with diac subjects toled subjects is likely to be to likely is 0.6 . isorders , car The above results The above results Pooled analysis of 6,139 CI uterine leiomyoma uterine . .
s ; or . group Sitagliptin - As result a As . case cardiac d cardiac
on based or creatine phosphokinase creatine
the total observation period was was period observation total the . days after randomization in randomization days the after For the remaining the remaining For test results on safety parameters safety on results test carcinoma intestine ; and large which 5 eventsin 5 comments
’ ). there is no evidence suggesting that that suggesting evidence no is there Sitagliptin group Sitagliptin of
, performed performed years for the non the for years - increased increased seborrhoeickeratosis
; of was was
y higher in the Sitagliptin group than in the in the than group in Sitagliptin the higher y CK increased was determined to be asso tobe determined was increased CK patient musculoskeletal and connective tissue disorders tissue connective and musculoskeletal
atpresent, , increased during treatment with in the treatment during placebo increased 7 subjects
In these studies, these studies, . In
in taking into account that Sitagliptin Sitagliptin that account into taking
92 treatment difference with its 95% its with difference treatment - reductase inhibitor reductase subjects during treatment with Sitagliptin with treatment during 32 subjects subjects haemangioma of liver haemangioma
, and the and, the investigators 2 in prostate cancer prostate
.) ; and but considers that it is necessary to continue to collect collect to continue to necessary it is that considers but the relationship the However, CoA
entified, but there were no adverse adverse no were there but increased notcould be identified, between ,
, determination
other
;
occurred For HMG- ( .
s musculoskeletal and connective tissue disorders tissue connective and musculoskeletal isozyme colon cancer colon
; an adverse event of CK of event adverse an . disease cardiovascular days after randomization in the non- the in randomization after days ) studies III phase and II phase term treatment studies with with studies treatment term skin papilloma skin increased increased 12 exposed 18 tofor 106 weeks exposed ;
( 2.2% vs. 1.6% vs. 2.2% disorders tissue connective and musculoskeletal
with ( gn of the cause of CK of cause the
(28 events)
as . ),
rs s a si but a causal relationship to the study drug was denied for all all for denied was drug study the to relationship causal a but . acceptable is response
neuroma term treatment studies treatment term - up and 230
s wa ; ’ years for the Sitagliptin group and 2,270 and group Sitagliptin the foryears increased was determined by the investigator to be associated with exercise or exercise with associated be to investigator the by determined was increased - Relationship to ) Relationship lasm malignant lasm
.3
abetes mellitus abetes asked the applicant to discuss to discuss the applicant asked there was no consistent trend in the development of tumors etc. in the in etc. tumors of development the trend in consistent no was there that understands no consistent trend in the development of tumors etc. etc. of tumors development the in trend there is no consistent that blind phase blind .(3) categorized nts were reported nts reported were eve adverse serious Seven follows: as considers
- patient . applicant Sitagliptin group
increased increased he ECG and other laboratory parameters, etc parameters, laboratory other and ECG 2 subjects including 2,994 foreign clinical studies clinical foreign type 2 di slightl treatment was group by etc. tumors of incidence non- The mean number of days to onset of malignant tumors was 241 was tumors of malignant to onset of days number The mean gro Sitagliptin , discontinuation indicate cases) gastric cancer gastric disorders An adverse event of CK of event adverse An , background patient the on based discussed was increased of CK ded as follows: ded respon The applicant T PMDA PMDA 4.(iii).B PMDA long Japanese ( ( double CK information on the development of tumors etc. after the market launch market the after etc. of tumors development the on information neop hepatic event of CK of event labor for 22 subjects medication concomitant with events events protocol did not require CK require not did protocol observed in Japanese - inobserved Japanese long disorde or cardiac
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page93
,
) g. e.
, 4.0% insulin ( subject subject
reported 1 ases were ) Allevents c . pioglitazone otherserious causality was was causality l (
after the market market the after al ncreased adverse events of of events adverse inadequate glycemic glycemic inadequate myocardial ischaemia myocardial adverse reactions adverse in both groups and the the in both and groups
, respectively , development of oedema oedema of development or it is necessary to collect tocollect necessary is it , serious adverse events in 18 in18 events adverse serious
the applicant to discuss the the to theapplicant discuss adverse events of hypertension, hypertension, of events adverse ) subjects disorders cardiac possible is associated with i with associated is asked asked
66
of the 19 and and . the the 353 patients with type 2 2 the type with 353 patients ) among of Foreign Study), P019 s subjects of the Sitagliptin of subjects the group Sitagliptin 2 10), ( 7 and deterioration of hypertensive complication complication hypertensive of deterioration
PMDA
, when used concomitantly with concomitantly used , when in .
, P055 Study In patient no serious adverse drug reactions were reported reported were reactions drug adverse serious no 5435- . 764) , P054 etc. Therefore,Study in that to similar was pioglitazone on adipocytes
lications comp deterioration of including
( 175 175 group and there was also no clinically relevant relevant clinically no also was there and group 93 . Thus, . 759-
failure of cardiac se events , and 3.0% ONO-
, hypertension the with 3 subjects Among an adverse drug reaction drug adverse an as classified GIP ), P054 ) ( occurred (
Weight increased was observedwas increased Weight
). adver was was
on adipocytes )
musculoskeletal musculoskeletal with associated to be no subjects 2 subjects of the Sitagliptin group (1.1%) and 1 subject of the the of subject and 1 (1.1%) group Sitagliptin the of 2 subjects , P055 Study Japanese
2.8% oedema oedema
As the subjects with hypertension did not experience increased increased experience not did hypertension with the subjects As ( 66 , 2008; 25: 2008; ,
event atment study atment of 1 ( known
1 s, in patients with type 2 diabetes mellitus type with patients s, in ( , but a causal relationship to Sitagliptin was denied for for denied was Sitagliptin to relationship causal a but ,
)
peripheral peripheral occurred in occurred ncrease the cardiovascular risk cardiovascular the ncrease of pioglitazone had who patients diabetic 2 type in studies Sitagliptin
term tre term the action of elevated 1.5% 2 , P019 Study In to i Diabetic Med Diabetic blind comparative study comparative blind - edema considered to to be considered not were cases these blind phase were examined in detail in examined were blind phase O , ” assessable the Sitagliptin 100 mg ( group mg 100 the Sitagliptin - . disorders tissue and connective musculoskeletal . In a long . - In ), subjects Safety in) Safety combination therapy with Safety in) Safety monotherapy reductase inhibitor ouble as “un as Flatt PR, PR, Flatt 66 pioglitazone monotherapy ( monotherapy pioglitazone
.5 .4 ( d loss ofloss consciousness cardiovascular disease, or fluid retention or disease, cardiovascular and weight increased were reported in the Sitagliptin 50 mg group and their incidences were were incidences and their group mg 50 Sitagliptin the in reported were increased andweight of
, .(3) .(3) considers as follows: as considers 3 group of placebo subjects the CoA ( bo group (0.6%) and (0.6%) bo group
5
MDA been reported that that reported t been has . retention dueto fluid . aggravated as hypertension reported weight or oedema were inreported . discontinuation drug study without resolved , which hospitalization required 2 other wasthe classified and event adverse as a serious mellitus diabetes and oedema theduring oedema, 4.5% control on control The applicant responded as follows: as responded The applicant theBased from on data 4.(iii).B P double a phase III, In 4.(iii).B place with drugs usedconcomitantly HMG- I in the Sitagliptin group, as in voglibose the group, in the Sitagliptin hypoglycaemia information on on information subjects, subjects, determined . launch resistance resistance use the of pioglitazone during be noted should Sitagliptin for potential the action antagonizing by adverse events and the incidence of hypoglycaemia incidence the and events adverse no major safety problems with Sitagliptin monotherapy with Sitagliptin problems are safety there no major
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page94
, blind . - 33 he above
the T blind . - in pioglitazone
demonstrated demonstrated in Table inTable
was
) )
no major differences no major ) ) ) ) ) )
) according to gender or to gender according 45 mg 1/31 0/31 2/38 0/38 2/38 2/31 21/38 18/31
( ( ( ( ( ( ( (
P055 + complications
3.2 0.0 5.3 0.0 5.3 6.5
Sitagliptin ) 55.3 58.1 as presented
30 mg
Study Study
( ) )
. in group the placebo Males ) is unlikely to cause an increased increased an tocause is unlikely ons between the Sitagliptin and and Sitagliptin the between ons ) ) ) ) )
explained that there are no major no major are that there explained , there were ) , etc. kg 4/38 0/38 0/38 4/49 0/49 0/49 26/49 23/38 ( there was also no clinically relevant relevant clinically no also was there ( ( ( ( ( ( (
,
Placebo ) 0.0 0.0 8.2 0.0 0.0 P055 the dose of pioglitazone of by the dose 10.5 53.1 60.5 Pioglitazone 12
) )
) ) ) ) ) ) pioglitazone
the safety profile in the double the in profile 08), the safety the applicant pioglitazone 0/35 2/35 2/28 1/28 0/28 2/35 17/28 20/35 ( ( ( ( ( ( ( (
7 metformin
15 mg . As 5. 0.0 5.7 7.1 3.6 0.0
Sitagliptin
of the combination therapy the of combination 60.7 57.1 94 5435- -
and adverse drug reactions
) ) ) ) ) ) ) )
Females No. of cases included in safety analysis safety in included cases of No. / safety ONO in the safety profile between the double the between profile in safety the seen were Treatment Week Week Treatment 1/30 0/30 0/30 1/19 0/19 0/19 16/30 13/19 ( ( ( ( ( ( ( ( ( (
combination study ( study combination
Pioglitazone
the Placebo events
0.0 0.0 0.0 3.3 0.0 5.3
53.3 68.4
.
in and 1.5 the Sitagliptin group
Treatment Week 52 Week Treatment
blind phase - pioglitazone pioglitazone nd combination therapy with therapy combination No. of cases with (
adverse event adverse event 33. Clinical adverse events
% combination study study combination . cant to discuss the safety by gender and and gender by the safety to discuss cant Oedema increasedWeight Oedema increasedWeight Table Table Sitagliptin combination therapy therapy with combination Sitagliptin Specific Specific Treatment group Adverse events reactions drug Adverse Specific Adverse events reactions drug Adverse
of serious adverse events or adverse drug reacti drug adverse or events adverse serious of Incidence Incidence Sitagliptin and no major differencesand no major in the double
, Safety in) Safety combination therapy with metformin combination study (P055) study combination with .6 pioglitazone considers that the safety of Sitagliptin combination therapy with pioglitazone was pioglitazone with therapy combination of Sitagliptin safety the that considers .(3) Treatment Week 12) a Week Treatment asked the appli the asked
considers that the safety of Sitagliptin combination therapy with metformin metformin with therapy combination Sitagliptin of safety the that considers . response the accepted azone (
no increases in adverse drug reactions characteristic of ubgroup analysescharacteristic reactions drug in adverse ofincreases Study no showed P055 incidence of cardiovascular adverse events or deterioration of cardiovascular deterioration or events adverse cardiovascular of incidence PMDA results indicate that indicate results pioglitazone 4.(iii).B PMDA inthe because demonstrated S pioglit as follows: responded The applicant 1.8 kg was weight in body change because in a because PMDA there were no major differences in differences no major were Thus, there in occurrence the placebo groups the dose of the dose hypoglycaemia phase differences in the safety of the combination therapy according to gender or the dose of dose the or gender to according therapy combination the of safety the in differences PMDA
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page95
, : ) a ) the the SU 12
with were
week week in draft
( the , and no , and no and 12- contains contains concluded 1 mg/day 1
( there was a a there was 11.5%
, a lower dose a lower dose The reported were similar similar were , period demonstrated demonstrated er dose of the the of er dose patients patients
.
ies ) also 12) was PMDA ation combin other
a low
. Treatment Week Week Treatment draft ( or
package insert insert package treatment associated with with associated
of glimepiride of
ar relationship between the the between ar relationship start with Taking accountTaking of the above glimepiride .
.
blind phase SU agent, start agent, SU with the incidences of serious adverse adverse serious of incidences the monotherapy monotherapy a Treatment Week Week Treatment agent, agent,
( ) 3 mg/day
hroughout the hroughout to t SU 09), the applicant to discuss the relationship relationship the discuss to applicant the with ( - other therap combination ;
or ion with with ion 3% hypoglycaemia - there was no cle no was there 5435 - asked , tagliptin and placebo groups and there were no no there were and groups and placebo tagliptin hypoglycaemia
0% than in other combination studies ( studies combination other in than with increasing dose of glimepiride of dose increasing with included in the Sitagliptin the in included glimepiride
doses of 1 of doses
causality and the dose of glimepiride of dose the and causality ONO 95 glimepiride ( sulfonylurea 09) PMDA - and and However there was no clinically relevant hypoglycaemia relevant clinically no was there , monotherapy monotherapy , ). 5435 Thus, . with with on study on study )
, while at the while , in order to reduce the risk of hypoglycaemia of risk the reduce to order in 20.7% hypoglycaemia an adverse event of event adverse an
ONO- 3% adverse events inthe Sitagliptin group tended to be higherin a , ( - overseas labelings, the Japanese package insert ( insert package Japanese the labelings, overseas the occurrence of of occurrence the and in order to reduce the risk of hypoglycaemiarisk of the reduce to order in combinati 0.7% - double the between profile safety the in the time to onset to time the
. the response andaccepted is appropriate none of the of none and severity in moderate or mild all were
phase III clinical studies, studies, clinical III phase , glimepiride
.
3 mg/day 3 the number of subjects with hypoglycaemia was small, i.e. 3 subjects, at at 3 i.e. subjects, small, was hypoglycaemia with subjects of the number
was similar between the Si the between similar 12) was ; hen Sitagliptin is is in Sitagliptin combinat used hen combination therapy therapy with combination 09, poglycaemic poglycaemic 52. As with - the study due to the study hy 8.8% were seen that the safety of Sitagliptin combination therapy with therapy combination Sitagliptin of safety the that
with , glimepiride s
5435 that, w - from combination study study combination Safety in) Safety combination therapy with
.7 5.6% be considered may has been has statement caution following the
,
, stating stating consider blind blind in phase the .(3) f 4 to 6 mg/day of f 4 to 6 mg/day
Treatment Week Week Treatment
2 mg/day - differences ( ies
.” term treatment studies, studies, treatment term ; Treatment Week Week Treatment agent agent hen Sitagliptin is used in combination with a with combination in is used hen Sitagliptin
he incidence of of incidence he W vents of hypoglycaemia “ SU agent discontinued discontinued findings severity of hypoglycaemia of severity e 7.0% caution statement caution that such between the dose of glimepiride of dose the between follows: as responded The applicant ONO Study In trend incidence higher towards of caution caution of SU the agent considered be may and particular problems with the safety profile up to Treatment Week 52, includingWeek hypoglycaemia Treatment to up profile safety the with problems particular symptoms gastrointestinal doses o doses events and adverse drug reactions in the double blind phase blind double the in reactions drug adverse events and placebo groups and Sitagliptin the between major because in the because PMDA 4.(iii).B phase long- T double therap glimepiride combination therapy glimepiride therapy with combination
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page96
,
) ) ) ≥ ),
7 0 0 0
) ( ( ( (12
5 = 200 CR
(
71.4 ) n 0.0 0.0 0.0 C Present group (
09 - adverse
100, mg ) ) )
subjects ), subjects ) 0 5 0 63 ( ( ( Sitagliptin
5435
- 41 = 200
( 65.1 50, enrolled into enrolled into patients with there was no no there was Furthermore, Furthermore, n 0.0 7.9 0.0 Absent
154 . , 1036 ONO
, 25,
ere the of ) ) )
8
enal insufficiency enal
,
orabsence blind manner of 0 0 0 ) clinical studies in in studies clinical
0 17 ( ( ( -
-
. ) 11 =
( 64.7
82 n 0.0 0.0 0.0 110 Present ( ) group (
5435
mg ) ) )
placebo ) 7 1 0 ( ( ( ( Sitagliptin 128
ONO-
79 7.9% , 100 bsent = ( 61.7
5.5 0.8 0.0 A n ), in a double 80 mL/min
P055
, < ) ) )
) 6 1 1 64 ( ( (
CR
, the incidences of clinical the incidences , 36 =
P054 ( 56.3 n C , 9.4 1.6 1.6 Japanese Japanese all cross Present subjects ( a group 09)
-
) Safety analysis population analysis Safety A202 ) ) mg
( the incidences of clinical adverse events, events, adverse of clinical the incidences ) ,
6 3 28 ) ( ( Sitagliptin 385 (
1036
50 respectively, which were similar to those in in those to similar were which respectively, cy 194 = 5435 50.4
( - 1.6 0.8 Absent n A201 7.3 of patients with renal insufficiency renal with patients
(
) moderate renal insufficiency w insufficiency renal moderate
overall adverse events or adverse drug reactions reactions drug or adverse events adverse overall
)
the ) ) )
7 688 ONO 9 0 0 0 the presence presence the (
( ( ( (
studies
96 =
) n ), subjects 0.0 0.0 0.0 Present 08, 77.8
group According to According 80 mL/min
. ≥ weeks
mg llitus and and llitus ) ) )
154
CR ) 6 0 0 Sitagliptin 12 71 ( ( (
( 5435-
25 C
- ( 39 = of
( 54.9 n 8.5 0.0 0.0 Absent 7 accordingto ( blind
-
)
drug reactions, reactions, drug adverse events, adverse clinical of incidences The
ONO Absent ) ) ) . patients with renal insufficiency were 71.4% were insufficiency renal with patients ency, i.e. 66.4% ency, ), 2 1 2 21 37 ( ( ( ( d by dividing subjects 1,190
Due to the limited number of cases evaluated, there was a high a high was there evaluated, of cases number limited the to Due
an increased incidence of of incidence increased an no trend towards was butsubgroups, there =
, respectively , 4.5%
) n 5.4 2.7 5.4 Present the 56.8 , P055
34). an increased incidence of of incidence increased an , and studies where Sitagliptin was administered was Sitagliptin where studies
)
80 mL/min
)
) ) among 6 < by thepresence or absence of renal insufficien 3 5
( 18 167 ( ( 319 s (
( subjects
Placebo group
CR P054 =
C Table 1.6 0.9 Absent ( n 5.6 (
52.4
1036 ), subjects
, A202
nts of Patients with renal insufficiency insufficiency renal with Patients
of renal insufficiency of renal 154 )
. Clinical. adverse events in double
) ) 37 Special populations .1 34 ( N of
( s included included s
4) , A201 with type 2 diabetes mellitus mellitus diabetes 2 type with ( between patients with and without renal renal without and with patients between safety inthe differences explain to the applicant asked .( .(4) %
14 an increased incidence of of incidence increased an towards trend alsono was there and insufficiency renal with patients Table case ( reactions
and by the presence or absence of renal insufficiency were examined. As a result a As examined. were insufficiency renal of absence or the presence by and 3.6% Adverse drug drug Adverse patients without renal insuffici without patients cific adverse events or adverse drug reactions with increasing dose of Sitagliptin of dose increasing with reactions drug adverse or events adverse cific Adverse events ) Treatment group the in safety analysis in safety
renal insufficiency renal No. of Serious adverse events Presence or absence of Adverse eve to leading discontinuation patients patients and serious adverse events in events adverse serious and there was no trend towards towards trend no therewas in in reactions rse drug or adve events adverse specific based on the data from type 2 diabetes me 2 diabetes type with 3 patients only As Incidence Incidence follows: as responded The applicant performe was analysis Subgroup 4.(iii).B 4.(iii).B PMDA . studies clinical inJapanese insufficiency 80 mL/min variability in incidence in variability spe and the occurrence of adverse events in events adverse of the occurrence and Sitagliptin of dose the between relationship and r of absence or the presence by reactions drug adverse and events, adverse laboratory mg weeks) weeks) Renal insufficiency: Present 9.1% insufficiency renal events, laboratory adverse events, and adverse drug reactions by dose level dose by reactions drug adverse and events, adverse laboratory events, the
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page97
or or ) on ) ) As
) 31) and 9 )
26 34 ( renal ). ( (
65
groups cardiac 30,
35 /min *
Overall 13.8 40.0 52.3
** L ****
of ( P028
severe P028
Table Table ) ) ) ) ) 30 m Tables Tables ( 4 3
0 2 1 (
( peritoneal dialysis ( ( ( (
Study
< 29 ) ) ) 0.0 6.9 3.4 5 13.8 10.3
12 16 ( CR ( (
29 group C
Sitagliptin group groups 17.2 41.4 55.2 Stratum 2
between the two
[on hemodialysis or or hemodialysis [on s Sitagliptin group
**************
Stratum 2
with and those
) ) )
glipizide ) ) renalinsufficiency in Foreign
) 2 2 3
) ) 1 1
lipizide ( ( ( on hemodialysis or on ) ( (
glipizide ( or severe ( or severe g )
4 ) /
)
14 18 11 ] ( ( (
)
group the entire study period of period study entire the 9.1 9.1 36
18.2 18.2 27.3 /min L 11.1 out 38.9 50.0 Stratum 1
/min Placebo/ m ) was considered considered was group in Sitagliptin the
*********************** L ufficiency
in period after randomization after period in m - in total through
asked the applicant to explain the safety in in safety the explain to applicant the asked
) th
)
) stage renal disease renal stage stage renal disease ) - - ) 6 ) ) ) )
2 11 ( 5 ( ( to < 50
/min 2 1 3 0
(
( ( ( ( L in the run the in 26
. 36 / in placebo than the m cases to < 50 7.7
Overall : Coronary artery disease artery Coronary : 23.1 or end PMDA ter the initiation of rescue therapy 2.8 8.3 0.0 5.6 42.3 30 peritoneal dialysis peritoneal 13.9 97 )
orend
30 ≥
CAD
Sitagliptin group /min by degree of renal ins to < 50 ), ≥
L
CR *** as cardiac disorders disorders as cardiac
group 30
and C cardiovascular underlying disease underlying cardiovascular
CR adverse events reported in patients with moderate or severe or severe moderate with inpatients reported events adverse a cardiovascular disease category before randomizationin Study
adverse event
/min
≥ CAD ) )
30 m )
C 2 5 L Stratum 1
0 an
( ( ( CR < (
by degree of renal insufficiency
( C 11
( CR ) ) ) ) ) lipizide
0 0 0 0 0 lipizide g 0.0 C ( ( ( ( ( 18.2 45.5 / g (
Stratum 2
/
categorized 15 30m by severity including group ( ( 0.0 0.0 0.0 0.0 0.0
< es mellitus patients mellitus wi es dverse events occurring af Stratum 1, Stratum in underlying disease in underlying Placebo
( Placebo CR
* * * C ) ) ) 4 2 6 atients diagnosed with diagnosed atients
( ( ( on hemodialysis or on or hemodialysis on
[ 15 , studies clinical Japanese 2, about ) (about **** Excluding a ( in of the prevalence
26.7 13.3 40.0
Stratum 1
* of the data regarding of the there was a trend towards higher incidence of serious adverse events events adverse serious of incidence higher towards trend a was there s
)
were similar between the Sitagliptin and placebo and Sitagliptin the between similar were N ),
(
% Mild Mild Deaths and adverse events Death Overview of p s the difference Severe
. Stratum . disorders Moderate ( verall cardiac cardiac verall 35
36 O Treatment group in safety in analysis safety the higher severity of cardiac disorders observed observed disorders of cardiac severity the higher
Renal insufficiency Renal group in Sitagliptin the death, ncluding difference No. of cases included included cases of No. renal insufficiency insufficiency renal ),
Incidence Incidence Stratum2: Severe renal insufficiency Stratum 1: Moderate renal insufficiency renal Moderate 1: Stratum Table Table
ere 36 Atherosclerotic cardiovascular disease cardiovascular Atherosclerotic insufficiency ummary values values ummary
: renal disease stage ailure
) f
N
VD (
Including 1 subject who discontinued the study due to to due study the discontinued who subject 1 Including Table Table
insufficiency insufficiency . ***************************** * in 2 diabet type studies Two **************** % AS
in group the Sitagliptin patients with moderate with patients 2 diabetic type and there were also no differences in the severity of adverse events. Meanwhile, in patients with with inpatients Meanwhile, events. adverse of severity the in differences no also were there and moderate renal The applicant responded as follows: as responded The applicant The s end- . P028 Study ] dialysis peritoneal i disorders, there w there ( with associated in included cases of No. ASVD CAD Heart safety analysis safety
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page98
. the the the the the this this it is , in
cardiac hepatic , , increased increased , P017
Pugh class Pugh - insufficiency insufficiency ild ALT increased
, ] Ch were higher in were higher
to
In In Study . ALT . Japanese studies, AST studies, Japanese 1.2% ( [ or
cardiovascular underlying underlying cardiovascular term treatment studies ( studies treatment term . studies clinical inJapanese -
not essentially different from from different essentially not increased
similar between patients with patients between similar
long Sitagliptin increased increased increased ere ALT of each patient of each
the safety of Sitagliptin in patients patients in Sitagliptin of safety the .
Although patientsAlthough withsevere hepatic foreign studies foreign of equivalent level and .
) , P017 Study into enrolled not were
ese patients are patients ese C control ( o dose adjustment isand for no adjustment required dose Sitagliptin
increased
than in the in than
class class
in Japanese patients with moderate or severe renal renal severe or moderate with patients Japanese in 98
Sitagliptin is used in patients with severe hepatic hepatic severe with patients in used is Sitagliptin AST this finding. foreign studies, AST studies, foreign Pugh ss -
when when ; will be made taking account of comments from the Expert the Expert from comments of account taking be made will ]
primarily renally eliminated renally primarily the and is liver d by through carefulthrough observation Child of Sitagliptin of
5.1% in patients with moderate or severe renal insufficiency renal severe or moderate with in patients [
s response that there were no differences in the safety between between safety the in differences no were there that response s ’ asked the applicant to explain applicant the asked as well and healthy subjects and healthy Taking also into account that Sitagliptin is renally eliminated renally is Sitagliptin that account into also Taking
conclusion . P028
the incidences of the incidences PMDA , increased increased
dose a lower
he applicant he can be managed managed be can term treatment studies were compared to foreign foreign to compared were studies treatment term but but a final ALT the safety of Sitagliptin in Japanese patients with moderate or severe renal renal severe or moderate with patients Japanese in of Sitagliptin safety the patients with severe hepatic insufficiency hepatic severe with in patients , this
, using ] asked the applicant to discu the applicant asked As Patients with hepatic insufficiency insufficiency hepatic with Patients of equivalent level to level equivalent of has not been confirmed at present, it is appropriate to avoid the use of Sitagliptin in ofSitagliptin use the toavoid appropriate is it at present, confirmed been hasnot prevalence of the in prevalence differences there were some though )
. is insufficient to evaluate the the safety toevaluate insufficient is
3.8% .2 . [ between the the groups between
. PMDA .(4) s considers as follows: as considers ) dose pharmacokinetics of Sitagliptin in Sitagliptin foreign of dose pharmacokinetics subjects w ] - in patients with moderate hepatic insufficiency hepatic moderate with patients in atients with adverse events or adverse drug reactions of AST reactions drug or adverse events adverse with atients iciency and iciency tient population tient needed needed are tests additional o 1.9% [ disordersoccurred in the Sitagliptin renal groupmoderate with only the patients among 1) (Stratum disease The applicant responded as follows: as responded The applicant The p
- When Japanese long 4.(iii).B Discussion PMDA t understands PMDA with normal renal function normal with and those insufficiency renal mild with patients and Japan in studied been not have insufficiency renal severe or erate mod with patients However, Study inForeign moreover, information insufficiency pa As a clinical study a clinical As Japanese studies studies Japanese increased ) population safety pooled insufficiency has not been conducted, conducted, been C has not of profile isto the alter pharmacokinetic unlikely insufficiency and measures to be taken be to measures and function hepatic reduced with severely follows: as responded The applicant metabolize minimally is Sitagliptin As single insufficiency insufficiency moderate hepatic insufficiency hepatic moderate N insuff the pharmacokinetics of Sitagliptin in th in Sitagliptin of pharmacokinetics that the considered those
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page99
is or 65 the the the
1
, term ≥ - ), - death
results results
1 of these
drug ). subjects regarding GLP ) a caution
Am J Clin Clin J Am s commonly commonly there is no There were , , were related related were . C 522 large intestine intestine large as ( ,
he above he of patient including T of Sitagliptin in Sitagliptin of . were not associated associated not were Japanese long Japanese class class
21 ≥ 65 years who had ), hyperlipidaemia formation formation 31
, in patients aged in patients metabolized the of dies
However Pugh in had 3.8% 11 -
( et al. et G Musso,
( Adverse events leading to to leading events Adverse dizziness ) s , ). subjects aged aged subjects 37 35.5% a hepatically hepatically a nce background factors , increased weeks of treatment 10, up to 52 weeks i patient -
the S is well tolerated tolerated is well years who had their dose increased was was dose increased had their who years marketing safety in safety marketing ). . insignificant is Table Table - 31 ALT term treatment stu treatment term ( 08 to 65
≥ draft and the overall population of (the inactivation of both GIP and GIP both of inactivation (the and
between between
5435- hyperlipidaemia and steatosis hepatic
20
corresponding to Child to corresponding . illnesses the concomitant with associated ( 99 myocardial infarction myocardial
i.e. of Sitagliptin Sitagliptin of
and the and the overall ( population
increased ) increased
≥ 65 years who had their dose increased in the occurrence of laboratory adverse events between between events adverse laboratory of occurrence the in subjects aged aged subjects
64.5% , ONO- P055 ( the s steatosis and hepatic with obesity subjects
ie and
100 mg/day
, failure cardiac 116 differences AST of events adverse of incidences higher the that considered is it subjects aged aged subjects of observed in theobserved Japanese long - it is necessary to collect post collect to necessary is it
5
5 correlated correlated acute acute , Sitagliptin in patients in Sitagliptin , is
Thus,
. 567.), , but a causal relationship to the study drug was denied for all cases for denied was drug study the to relationship a causal , but 4.3% he applicant’s view that as Sitagliptin is not not is Sitagliptin as that view applicant’s he ) ears who had their dose their had who ears d it has been reported that GIP that reported been has it d increased
term treatment stud treatment term - term treatment studies were examined. As a result a As examined. were studies treatment term ALT - ≥ ≥ 65 y an increased dose of dose of increased an Elderly ) Elderly
gastric cancer gastric .3 . type 2 diabetes mellitus, mellitus, patientsdiabetes 2 with type , and
that in the overall population overall the in to that comparable in .(4) ma
considers as follows: as considers 100 mg/day of 100 dose increased of an the safety to explain applicant the asked cardiac failure cardiac 2009; 89: 558- 89: 2009; Sitagliptin Sitagliptin of safety the on insufficiency hepatic of t
hepatic steatosis hepatic had tients acute acute effec PMDA understands t understands PMDA PMDA with exposure to Sitagliptin, but were substantially but were to Sitagliptin, with exposure follows: as responded The applicant Japanese long In 4.(iii).B long Japanese pa with experience clinical hypercholesterolaemia Nut r, increased . steatosis hepatic the elderly the PMDA statement should be included in the package insert ( insert package the in included be should statement present AST of events adverse of occurrence tothe an studies treatment inhibited by Sitagliptin) by inhibited incidence of clinical adverse events in events adverse clinical of incidence ( also no differences in the incidence of hypoglycaemia of incidence inthe differences alsono almost almost in occurred discontinuation carcino their dose increased ( increased dose their Likewise, there were no major major no were there Likewise, subjects aged aged subjects that indicate . years
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page100
) ) ) ) ) ) 0 0 2 29 108 ( ( ( 552 ( (
=
0.0 0.0 0.4 n 5.3 (
19.6 , the On
Overall population * . )
, weeks
rather
10
-
52 ”
to
08 - the proposed proposed the
was filed was
Therefore ” 5435
Laboratory mprovement of of mprovement of the following of the following
i ) ) ” hase II and phase phase and II hase ( ) ) ) ) 3 0 0 0 18 s.
( ( ( ( ( blind phaseand ONO-
years who had their their had who years - a Japanese phase III phase a Japanese
＝116
2.6 0.0 0.0 0.0 n ( 15.5 65 years with dose increase
P055, that Sitagliptin improves improves Sitagliptin that (
≥
65
blood glucose and is well well is glucose and blood ≥ to any one any to Japanese p Japanese
weeks of treatment.
exercise therapy exercise . 52 type 2 diabetes mellitus diabetes 2 type diabetes mellitus diabetes , “ Subjects Subjects 10 - prandial confirmed
- is different from the indication in the the in indication the from different is
5435
) ) ) ) ) ) term treatment studies treatment term in type 2 exercise therapy exercise 2 57 - 451 26 14 (
( 552 ( ( (
ONO-
=
indication for Sitagliptin for indication 0.4 application for Sitagliptin forapplication Sitagliptin for , which n 4.7 2.5 10.3 ( hour post ) 81.7
in type 2 diabetes mellitu diabetes 2 type in 2-
Overall population cepted the response improvement of glycemic control in patients with with patients in control glycemic of improvement . In Study . In
“
100 ac
reactions in long indication would be indication .
therapy and /ortherapy drug drug blind phase blind - PMDA weeks of treatment for the placebo group in the double the in group placebo the for treatment of weeks
Clinical
Europe is is Europe
, which was used as the control drug for the drug as control used , which was / 40
) ) ) diabetes mellitus diabetes , ) ) ) 97 15 1 9 5 09 ( ( ( ( (
- prandial hyperglycemia
appropriate
therapy and/or therapy to dietary in addition - ＝116
s n 0.9 7.8 4.3 ( 83.6 12.9 years with dose increase 5435
table the
voglibose s 65 , ’
prandial hyperglycemia in type 2 - ≥
group in the double the in group ONO-
asmodified follows in foreign patients type with foreign control in of glycemic he of degree improvement
T exercise therapy only therapy exercise
post , and in to addition dietary .” 50 mg s /or
Subjects Subjects 08 d -
the applicant the
. studies clinical Japanese of tothe results similar was ovement of post of ovement
5435 sensitizing agent sensitizing t also fasting blood glucose and blood glucose fasting but also - from
the indication in the US the in indication the mpr i 1C
ONO- “
, ) Indication PMDA N . continuation
( Based Based on the above
5) . % proposed proposed the explain to applicant the asked a new a new (P054), study drug comparative blind, .( Clinical and laboratory adverse events and adverse
- improvement of improvement
.
“ prandialhyperglycemia
37 - Europe / Adapted by by Adapted
Incidence Incidence * of treatment for the Sitagliptin Sitagliptin the for treatment of In Studies P055 Studies In
2 diabetes mellitus diabetes 2 have mellitus diabetes 2 type with patients in studies clinical III HbA not only type 2 diabetes mellitus 2 diabetes type than PMDA post double of indication , hand other the
4.(iii).B As there were no major differences in the safety between the subjects aged aged subjects the between the safety in differences major no were there As Table US follows: as responded The applicant toReferring the indication for tolerated , population overall the and increased dose proposed indication will be indication will proposed (b) Use of sulfonylurea of(b) Use respond sufficiently do not who in patients only be used should Sitagliptin Type 2 diabetes mellitus; diabetes 2 Type [After modification] [After modification] treatments. therapy Dietary (a) an insulin of (c) Use
se events Adverse events leadingto dis Deaths Serious adverse events Adverse drug reactions drug Adverse Adver
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page101
s ” the ere q.d. mg w izing izing s n that n that
25- groups groups the A
, . ≥ considers considers in healthy in healthy in type 2
Sitagliptin Sitagliptin
sensit
)
” should be ” should the wording s it is appropriate is it appropriate
A112 regimens as to PMDA , dependent manner dependentmanner exercise therapy, exercise activity increased increased activity ,
, support - marketing data on data on marketing
50 mg b.i.d. 50 mg -
that combination therapy therapy combination hour weighted mean hour weighted mean
4 - (d) Use of biguanide of Use (d) - etc. d b.i.d. A111 Sitagliptin combination combination Sitagliptin and (
a dosea and/or
he weighted mean percent percent mean weighted he
However ies q.d.
there were no significant significant were no and, there conclude
and t lowering effect of Sitagliptin 100 100 Sitagliptin of effect lowering fold higher following , - insulin with drugs as therapy prandial hyperglycemia 2-
- of Sitagliptin Sitagliptin of With respect to respect With 100 mg 100
phase II clinical study in patients with with patients in study clinical II phase ≥
the wording of “ of wording the PMDA .”
s A of Sitagliptin as follows: as Sitagliptin of On the other h the On exercise therapy therapy exercise
As to dependently the Japanese term for “biguanide term Japanese the regimens -
/or ,” comparable efficacy was demonstrated was efficacy comparable
was about was dosing
and appropriate wording in the indication section would in section the indication wording appropriate , it is recommended that post is recommended , it the Sitagliptin Sitagliptin the b.i.d. of Sitagliptin increased in increased Sitagliptin of
101
n taking into account very that is ofbuformin use the the daily been approved have , , - sensitizing agent sensitizing both
- improvement of post improvement AUC in addition to dietary to addition in therapy
inJapan s
compared to placebo. to compared and phase I studmultiple oral dose I phase and sulin - the blood glucose to evaluate
the percent inhibition of plasma DPP of plasma the inhibition percent in and there are no data on combination therapy with buformi therapy combination on data no are there and for once for exercise therapy exercise no major differences between the q.d. and the between differences major no
concentratio “
metformin . response the accepted and mellitus” es For the primary endpoint in of change 24 the primary For the 1 are - ) P013 . the plasma plasma the
Sitagliptin concentration Sitagliptin dosage regimens and regimens dosage and/or
as is submitted in this application application this in submitted data study the clinical
. group to placebo the compared of Sitagliptin of indication from “ from indication (A203) enient for patients was chosen and phase III clinical studies were conducted. conducted. were studies clinical III phase and chosen was patients for enient
100 mg q.d. and 50 mg
the rationale sensitizing agent sensitizing
- was conducted was
” rather than s therapy in addition to dietary in addition the
s b.i.d. showed that showed although although support support this application in data submitted the study clinical , studies these In biguanide and plasma
, ” to “type 2 diabet “type ” to as . , plasma active GLP active plasma Dosage regimen ) Dosage between as compared to metformin to as compared 1 multiple doses multiple
). biguanides thiazolidinediones and biguanides in Dosage and administration and administration 6) Dosage icant explained icant and 50 mg 400 mg .(6 .( inJapan
daily daily dependently thiazolidinedione - - (c) Use of insulin of Use (c) s reduction significant
not only efficacy but also safety also but efficacy that only not clinical (A203) demonstrated the II study phase q.d. “
phase I single oral dose study ( single oral study phase dose I aking account of the results of clinical studies of Sitagliptin, Sitagliptin, of studies clinical of results the of account aking uncommon . be collected should buformin therapy with combination is classified as a as is classified in to addition dietary therapy with pioglitazone, a thiazolidinedione a with pioglitazone, therapy be “ biguanidea with metformin therapy with combination comparable comparable As
4.(iii).B 4.(iii).B T biguanide of (d) Use subjects adult male Dosing frequency Dosing frequency (a) The appl A diabetes mellitus diabetes of although although action . modified to modify the proposed to modify dose up to increase increase mg 4, Week Treatment to baseline from glucose differences between the two two the between differences above results indicated that there that indicated results above regimen that is more conv is more that regimen had once mellitus type 2 diabetes
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page102
’ and term - in the of the , without without
long
dosing tolerability tolerability
once daily. 50 mg or little concern about little about concern is
daily daily - ) as follows: ffect of food on the the on food of ffect efficacy and safety were were safety and efficacy safety
whether or not the timing the or not timing whether , it is necessary to collect to collect is necessary it in expectation in expectation of its its has not been specified in the in the beenhas specified not Sitagliptin administered once once administered Sitagliptin
in consideration of patients of in consideration s lunch or evening meal evening or lunch
on . there is alsothere without specifying the timing of of timing the specifying without section and administration
However . Thus, ience and the pharmacokinetics or pharmacokinetics the influence not Sitagliptin administered administered Sitagliptin with conducted clinically no clinically has food that shown has dosing
The dose of Sitagliptin and in foreign countries where Sitagliptin is Sitagliptin where countries foreign in and ( . surveillance marketing
conven - suggested that the efficacy of Sitagliptin is is of Sitagliptin efficacy the that suggested does
before or after daily regimen regimen daily ’
daily daily
- ) ) P076 - , (
in the dosage the in
s once 102 A203
no meaningful effect no effect meaningful Sitagliptin 2,
Taking account of these points, points, these of account Taking or food. with taken without
A20 indicated that the pharmacokinetics of Sitagliptin is very is very Sitagliptin of the pharmacokinetics that indicated
, after breakfast after . section administration and (
he Sitagliptin pharmacokinetic and pharmacodynamic data from data from and pharmacodynamic pharmacokinetic he Sitagliptin
the timing of dosing relative tomeal relative of dosing timing the A112 ) P076 and thus has T has been has improvement of glycemic control by Sitagliptin was evaluated in in evaluated was Sitagliptin by control glycemic of improvement rationale for rationale (
, ,
dosage ). compromised even when Sitagliptin is administered at lunch or evening at or evening lunch is Sitagliptin when administered even compromised
a clinical pharmacology study assessing the e assessing study pharmacology clinical a in consideration of patients of in consideration
A111 the time of day of dosing of of day time the ( , , draft , in the the in Sitagliptin was administered before breakfast before administered was Sitagliptin
s
, Sitagliptin Sitagliptin , times of the day times
dependent pharmacological effects of, Sitagliptin effects dependent pharmacological - However Therefore good compliance good timing of dosing relative to meal of relative dosing timing affected by food. by affected
. nsufficient, the dosage may be increased up to 100 mg once daily mg up to 100 be increased may dosage the nsufficient, in which , despite that the that despite ,
). ) Dose has been has study clinical or III phase II o phase Furthermore 2 the N . ). . no major problem with recommending once recommending with problem major no asked the applicant to provide a justification for recommending once recommending for justification a provide to applicant the asked .(6
considers as follows: as considers subjects were required to take the study drug before breakfast and and breakfast before drug the study totake required were subjects is , Timing of dosing of Timing he applicant responded as follows: as responded applicant he PMDA package insert package studies clinical T If is i the effect 4.(iii).B daily evaluated of Sitagliptin pharmacokinetics the on effect meaningful PMDA effect food assessing study clinical Japanese The In all Japanese and foreign phase II and phase III clinical studies with studies clinical III phase and II phase foreign and Japanese all In (b) the with choosing problem no that there is . convenience specifying dose dose the explained applicant The ynamics of Sitagliptin of ynamics pharmacod the glucose given once daily at other at daily once hypoglycaemia of maintenance there there already on the market the on already evening, etc. evening, meal time meal studies clinical Japanese Japanese package insert ( insert package Japanese dosing relative to meal to relative dosing unlikely tounlikely besubstantially pharmacokinetics of Sitagliptin of pharmacokinetics tounlikely be of dosing affects glycemic control has not been investigated been not has control glycemic affects of dosing post via and efficacy of dosing timing the on information
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page103
. , ). the had 387
dose little little once 1% were
- group a
of of adverse between from
is change in 65 t
( (
or achieved or
whereas the the whereas once daily if an increased increased an as the usual as the usual Sitagliptin at at Sitagliptin
100 mg 100 here were no . 200 mg ecific
200 mg , g T term treatment treatment term . value value with with 16.8% differen
weeks. As a result As weeks.
or sp
long- 1C 100 m ly
term treatment study treatment term once daily in patients once daily event measured at 12 weeks weeks 12 at measured - 12 studies combined) studies
and and the 4 1C at 12 weeks after after weeks 12 at
HbA
up to safety of Sitagliptin among among of Sitagliptin safety problem
HbA (A202) was conducted where where conducted was (A202) or 100 mg 100 mg specific 7.0%
in the adverse drug reactions reactions drug adverse in the Sitagliptin Sitagliptin the in
. group thethan placebo in group < and a long lasses (SOCs) by
safety with C
adverse drug reactions drug adverse 1C , to placebo compared ased ased
09) - rgan dependent increase in the incidence of incidence the in increase dependent HbA 200 mg 200 dose increase in dose increase 5435 an - particular or fasting blood glucose met the criteria for for criteria the met blood glucose fasting or the difference from placebo was about about was placebo from difference the by SOC or or by SOC
( the dose was to be increased to increased tobe was the dose
s reduction their 1C , NO diabetes mellitus diabetes no ystem O ystem increase the before dose
of the patients O
who had an even lower lower even had an who s ) etc. glucose, blood
)
from baseline to Treatment Week 12 Week Treatment to baseline from either either
HbA after
103 achieved 08, of an increased dose of dose increased an of
1C - , seems if
, once daily patients patients significant prandial 5435 7.0% -
laboratory adverse events or events adverse laboratory there who had their dose incre dose their had who
showed no particular differences in the efficacy the efficacy in differences particular no showed
≥
- a dose towards rend
) of the recommended clinical dose recommended as the chosen been has 50 mg/day
1C ONO- 50 mg were similar were mg 50 or placebo was administered once daily for daily once administered was or placebo no t
once daily lecting a dose that is slightly more effective numerically effective more is slightly that a dose lecting
≥ A202 e
provided ( hour post patients 238 of 387
of also . S 2- (
in patients with type 2 type with patients in , P055 all all ,
compared to thecompared value ( there is no particular problem with choosing 50 mg/day with choosing problem no particular there is
200 mg clinical or laboratory adverse events or events adverse laboratory or clinical increase a dose with allowing no major problem
adverse reactions adverse drug specific S no specific but there were
doses with an HbA with 61.5%
or and value ,
the On theOn other hand, 200 mg 200 Thus, . 1C . the other Sitagliptin dose groups were groups dose of other Sitagliptin the ach not significant at , a goal of glycemic control of, a goal glycemic 100
e to in order to evaluate the effect evaluate to inorder
1C patients and there was in of terms in 50, , results these on Based
particularly higher incidence in the Sitagliptin Sitagliptin the in incidence higher particularly 25 7.0%
10),
a - inadequately to 50 mg to inadequately se during treatment with 50 treatment mg se during HbA < 25,
nsiders as follows: of the
1C fasting blood glucose blood fasting dose increase to 100 mg ( to increase mg 100 dose co 5435 , s)
- , studies these 4 In a 1C . HbA he incidence ONO In phase III clinical studies clinical III phase In . demonstrated ( Sitagliptin up to up of Sitagliptin safety and and the tolerability groups and Sitagliptin the placebo responding changes in changes for the primary endpoint of the change in HbA change the endpoint of thefor primary significant differences in the incidence the in differences significant Sitagliptin Sitagliptin clinical adverse events events adverse clinical the 50, 100, and 200 mg doses 200 mg 100, and the 50, patient the doses of of thedoses an
increase to 100 mg toincrease 100 study clinical II phase late A dose of 100 mg dose of PMDA HbA The late phase II clinical study clinical II phase late The daily dose increa was significantly higher only higher significantly was events adverse clinical of incidence The placebo group after after clinical significance clinical , group thanthe in placebo HbA lower even an There is also. There dose clinical the effect is insufficient because there were there were because is insufficient the effect . studies events with with events T
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page104
,
. he T . years years In the results results - efficacy
and then number of of number
, and skin , and skin ) t is necessary t is necessary results surveyresults the safety and and the safety it is necessary itis necessary I , , drug use draft investigated
a ield. , . considerable phase III clinical studies clinical III phase takingalso account of worldwide aking into account that the the that account into aking as cardiac disorders , t , As a As
. period observation and , information
, 3000. survey inhibitors 4 - results survey will be survey results - , surveillance agent in diabetic patients is required when when required is patients indiabetic agent
DPP results the planned duration of the survey is 3 the of survey the duration planned , marketing surveillance plan surveillance marketing showed no differences in the safety or safety the in differences no showed -
have renal or hepatic insufficiency hepatic or renal have
to be lower in Japanese patients than in foreign inforeign than patients Japanese in be lower to
10)
marketing surveillance protocol ( protocol surveillance marketing - or marketing - 104
- - use week
antidiabetic Although the use of Sitagliptin in children and pregnant and pregnant in children the of Sitagliptin use Although 5435 term treatment with Sitagliptin, including the occurrence occurrence the including Sitagliptin, with treatment term 24- - data items to be collected tobe items data
. the applicant to further consider the details of the survey, survey, the of details the consider further to theapplicant novel novel
- long ONO term safety data on data safety term - - use the rare via , if these collected emely are patients 09, nformation on the safety and efficacy of Sitagliptin in patients with with of in Sitagliptin patients and efficacy on the safety nformation - i urging and the target number of cases is is cases of number target and the and Week 52. Week and , is
urveillance plan 5435 24 -
and other proper use other proper and uses drug routine under marketing ONO - PMDA
musculoskeletal and connective tissue disorders and connective musculoskeletal 08, of the survey , -
y will be determined be will cacy marketing s marketing - xpected to be elderly be to expected are patients
between Week 5435 what kind of risk assessment should be performed in future in performed be should risk assessment of what kind
the safety and efficacy of a efficacy and the safety Post
treatment can be evaluated in a in evaluated be can treatment
initiation te 7)
.( ONO- observation period period observation The conducted. tobe is planned system registration central prospective, via considers as follows: as considers asked the applicant to explain a Sitagliptin post Sitagliptin a to explain applicant the asked
weeks from the start of Sitagliptin administration Sitagliptin of start the from weeks term approved overseas approved been have that class same the of drugs on other information safety marketing cardiovascular risk assessment of a of assessment risk cardiovascular - hypoglycaemia determine evalua 24 , P055 to isconsidered events cardiovascular of incidence US, filingan application for a drug containing a new active ingredient in thediabetes f . patients , of cases number the appropriate including Based on the above, PMDA long accumulate to important is it As 4.(iii).B of ana outline post presented The applicant ( PMDA to of survey In order post In to collect responded asresponded follows: mellitus 2 diabetes type long- and effi the safety efficacy of Sitagliptin in these patients identified from the use from identified patients inthese of Sitagliptin efficacy women/nursing mothers will be will extr mothers women/nursing disorders and tumor development, via post via development, tumor and disorders post is from the from diabetic 2 type Sitagliptin of
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page105
, label label in type 5.3.5.1.7
dispensed to
the New Drug
been , 5.3.5.1.6 in ,
iscussion. if it can be concluded that if be concluded that can it
mistakenly mistakenly 5.3.5.1.4
the new drug application. As a a As application. drug the new on the product. on the
had the study drug for- the open drug the study in , GLP/GCP inspection and data inspection anddata GLP/GCP d e
Data Submitted Data , 5.3.5.1.2 was conducted in accordance with the the with accordance in conducted was based
- Sitagliptin of Sitagliptin safety and efficacy the submitte concluded that there should be no problem problem be no should concluded that there
blind phas - ated data
5.1.1, 5.3. (
site inspection site - 105 oncerning the the oncerning for the the for C
PMDA Assessment the new drug application drug new the ance ance
it was found that at some clinical trial sites, sites, trial clinical some at that found was it in
concluded that there should be no problem with conducting a regulatory review review a regulatory conducting with problem be no should that there concluded
he submitted data have demonstr have data submitted he
gulatory review based on the submitted documents submitted the based review on gulatory PMDA based inspection and reliability assessment reliability and inspection based - submitted
As a result, a result, As but , ). site inspection took place in accordance with the provisions of the Pharmaceutical Affairs Act Affairs Pharmaceutical of the provisions the with place inaccordance took site inspection - data instead of the study drug assigned for the double the for assigned drug study the of instead
, PMDA’s conclusion on the results of document of results the on conclusion PMDA’s a subject
GCP on It isIt that t concluded reliability assessment reliability for the PMDA’s conclusion on the results of GCP on GCP of results the on conclusion 2. PMDA’s 1. document A Compli of Results III. provisions of the Pharmaceutical Affairs Act Affairs the Pharmaceutical of provisions . mellitus 2 diabetes mellitus 2 diabetes of type for be approved indication the may Sitagliptin there are no particular problems, taking account of comments from the Expert D the Expert from accountof comments taking problems, particular no there are Evaluation Overall IV. based on the submitted application dossier. dossier. application submitted on the based Application by and Conclusion PMDA Thus, problems. no particular there were result, 5.3.5.2.1 phase with conducting a re with conducting
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page106
, , to edical edical
M opinions opinions 2)
a reduced ’ eliminated July 8, 2009 cardiovascular cardiovascular
As it is difficult difficult is it As :
. dance accor in with
administered insufficiency are limited limited are insufficiency among the patients with with the patients among
be
patients considered to have to have considered patients , harmaceuticals and and harmaceuticals may
1) 2) it is appropriate to the isit avoid appropriate use of Expert Discussion were nominated were Discussion Expert
sought the expert advisors expert the sought Ono Pharmaceutical Co., Ltd. Co., Pharmaceutical Ono
the taking account of discussions with the the with discussions account of taking 100 mg 100 mg , to the patient
1) 1) 2) . Thus, , , 2)
(
PMDA) ( patients with renal insufficiency renal with 2 diabetic patients type
50 mg dated December 25, 2008). December dated /2008 50 mg in Japanese patients with moderate or severe renal renal severe or moderate with patients Japanese in in
1)
2) , in patients with renal insufficiency renal with in patients , clearance creatinine on based insufficiency renal the Sitagliptin Sitagliptin onlythe group 106
No. 8 No. also P028
25 mg
Expert Discussions etc. by P by etc. Discussions Expert Review Report Review
Taking also into account that Sitagliptin is renally is renally Sitagliptin that account into also Taking
.
prevalence of the prevalence in differences some there were . and moderate The results of the review ). 1 nyu Pharmaceutical Co., Ltd. Co., Pharmaceutical nyu Convening Convening
Ba Januvia Tablets Glactiv Tablets 25 mg Tablets Glactiv December 10, 2007 December Sitagliptin Phosphate Hydrate Phosphate Sitagliptin for
the following comments on the above conclusion by PMDA by conclusion the above on comments following the
between the groups the between Rules
PMDA Administrative Rule Administrative PMDA s in Japan. In Foreign Study Foreign In Japan. in described above, the safety of Sitagliptin in Japanese patients with moderate or or moderate with patients Japanese in Sitagliptin of safety the above, described are reported below. The expert advisors for advisors expert The below. reported are ” ( to evaluate the safety the evaluate to insufficient is ,
, registration for submitted product the concerning etc. declarations As
this patient population patient this
studied gency renal insufficiency based on their serum creatinine levels etc. etc. levels creatinine serum their on based insufficiency renal useful to allow the use of Sitagliptin Sitagliptin of use the allow to useful A
concluded as concluded follows: proprietary name] name] proprietary little - Pharmaceuticals and Medical Devices Agency Devices Medical and Pharmaceuticals draw a clear line between mild mild between line clear a draw
evices evices expert advisors based on the Review Report ( Report the Review on based the of“ provisions renal with topatients administered be can that agents antihyperglycemic Oral and is it to be administered should Sitagliptin or whether not determine moderate based on their on based Sitagliptin in Sitagliptin t present at confirmed been not has insufficiency renal severe insufficiency. insufficiency.
[Applicant] The expert advisors made advisors expert The PMDA has insufficiency renal or severe moderate with patients diabetic 2 type in of Sitagliptin safety The been insufficiency renal with patients in 1. Use The Review the of II. Content D in occurred disorders cardiac of events adverse though insufficiency renal moderate I. Submitted Product Registration for name] [Brand
underlying disease underlying the information the [Date of[Date application] [Non
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page107
. . ’s at mg and that drug drug drug were study
PMDA - 12.5 PMDA . , fied ] fied in orderto
insufficiency speci speci type 2 diabetes type 2 diabetes hen Sitagliptin is is Sitagliptin hen considering considering dose adjustment dose w ency and asked the the asked and ency the dose for patients patients the for dose and and
” surveillance of developing a developing of
marketing marketing study in type 2 diabetic - marketing marketing - study and **** study atients with with atients , hand other the On . ncluded as follows: as ncluded may be considered be may marketing ons co a post - is appropriate, is appropriate, ent moderate renal insufficiency renal insufficiency moderate ****
possibility
after the Expert Discussion the Expert after further reduce reduce further e.g. ( 3. Post SUag patients with moderate renal renal moderate with patients , *********************** ******* ***** and study ee “ s
hen Sitagliptin is used in combination with a a with combination in used is hen Sitagliptin careful administration administration careful [ However, However,
in the package insert (draft) ( (draft) insert package inthe W
. “
s view on the the on view s **** ’
*********** 107
. through . Sitagliptin may be used in p be used may Sitagliptin on the premise that premise on the this patient population patient this in to be contraindicated has ptin included ,
proposed commercial formulation at at formulation commercial proposed the with is impossible foreign
it is necessary to conduct a post to conduct is necessary it ) appropriate ] , *************
the applicant the mg
pe 2 diabetes mellitus with mellitus diabetes 2 pe was carefully observing their conditi observing carefully ty
have been studied in Japan and dose adjustment is impossible with iswith Japan impossible in and dose been adjustment studied have
for 25 )
s response patients with severe renal insufficiency including those requiring those including requiring renalinsufficiency patients severe with therapy with other antihyperglycemic agents antihyperglycemic other with therapy ’
while while
SU agent, a of lower dose the asked no
renal insufficiency renal lly eliminated and dose adjustment and dose eliminated lly caution statement caution . the since patients with renal insufficiency will be conducted to investigate the safety of of safety the investigate to conducted be will insufficiency renal with patients
PMDA of to investigate the safety of Sitagliptin in in Sitagliptin of safety the investigate to combination
the appropriate statement would be be would statement appropriate the , studies clinical Japanese moderate renal insufficiency insufficiency renal moderate
*********** the utility in the clinical practice as only 3 patients with 3 patients as only
with
, accepted the the applicant accepted
concluded that concluded . .
results survey results results survey results - - , Sitagli formulation commercial proposed
n of view as dialysis peritoneal or hemodialysis requiring those including insufficiency renal severe with patients use inSitagliptin with patients renal moderate insufficiency investigated in investigated Caution about 2. Caution PMDA PMDA The applicant explainedThe applicant as follows: in contraindicated be will Sitagliptin elevated be may concentrations plasma ********************* *********************** to applicant with patients above, the on Based I mellitus However PMDA Discussion, the Expert from comments the account of Taking of Sitagliptin mg 25 dose of used in combination with a used in combination with of hypoglycaemia risk thereduce including those requiring hemodialysis or peritoneal dialysis peritoneal or hemodialysis requiring those including present that considered the conclusion that the use of Sitagliptin should be avoided in patients with severe renal insufficiency renal severe with patients in be avoided should Sitagliptin usethe of that conclusion rena primarily is Sitagliptin present use formulation to allow for dose adjustment also in patients with severe renal insuffici renal severe with inpatients also adjustment for dose allow to formulation with moderate renal insufficiency [ renal insufficiency with moderate theOn hand other , dialysis peritoneal or hemodialysis
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page108
,
a the ced
Also FDA
” . caution
a marketing marketing marketing - -
new active
in Japanese inJapanese
uidance for uidance for rather than ). instructed ant to explain ant to explain g
” marketing safety safety marketing - draft This conclusion by This conclusion by (
the and sought the expert theand sought expert of cardiovascular events events of cardiovascular Thus, a post Thus, overseas post overseas lthough it is important to important is it lthough
pecial attention should be be should attention pecial containing a containing
s S ; When Sitagliptin is used in in used is Sitagliptin When . , including the occurrence of of the occurrence , including asked the applic the asked to be conducted, including its its including conducted, to be
may be enhan be may effect lowering iabetes, issued by the issued by 2 diabetes, ype - events cardiovascular other than SU agents, SU than other
, and skin disorders disorders , and skin disorders cardiac of
what kind of risk assessment should be be should assessment risk of kind what reat t reat PMDA referenced to referenced be increased be 4 inhibitors worldwide, it is necessary to to necessary is it worldwide, 4 inhibitors - cardiovascular risk assessment in diabetic indiabetic risk assessment cardiovascular surveillance surveillance may
DPP antihyperglycemic agents other than SU agents SU than other agents antihyperglycemic n antidiabetic drug n antidiabetic a ).
all n with a SU agent a SU with n combinatio in used when
herapies t to
t 108
draft n the US, s the blood glucose blood the s I marketing . - , taking also account of post account also , taking surveillance in accordance with with inaccordance are that will be modified as follows: “ follows: as bewill modified
) term treatment with Sitagliptin with treatment term the dose of a concomitant medication and medication a concomitant of dose the
ntidiabetic a draft data data - long (
a hypoglycaemia In addition, a In marketing
paid to the possible occurrence of hypoglycaemia of occurrence theto possible paid new - will be difficult in terms of feasibility of terms in difficult be will of term safety data on data safety term
. feasible the risk the of hypoglycaemia , this long- isk in r
Sitagliptin approved overseas. approved been have that class same of the ugs to confirm that the risk to confirm surveillance A thecontent of a post
occurrence hat as Sitagliptin is a drug with a novel mode of action and it is important to to important it is and action of mode novel a with drug a is Sitagliptin as hat the statement. thestatement. SU agent SU patients than in foreign patients, patients, foreign in than Japanese patients in lower to be e package insert e package
determine to determine necessary that is it considered
the applicant to applicant the include a in caution statement insert the package , disorders tissue connective and musculoskeletal modify ardiovascular PMDA taking into account that the incidence of cardiovascular of incidence cardiovascular account that into the taking in future, patients for Japanese The following comments were raised from the expert advisors: A advisors: expert the from raised were comments The following c , the Discussion Expert from comments the above .
the safety and efficacy of efficacy and safety the considered t considered was supported by the expert advisors expert the by supported was marketing surveillance surveillance marketing
- . response the accepted
instructed agents antihyperglycemic other with therapy combination
valuating for will be included in the package insert ( insert package the in included be will statement evaluate PMDA accumulate systematically 3. Post The statement in th in statement The a with combination The applicant responded as follows: as responded The applicant
be should attention agent, SU statement giving an instruction about an instruction giving statement to applicant paid to the possible PMDA hypoglycaemia, hypoglycaemia, post via development, and tumor information on other dr other on information PMDA performed performed expected is events ingredient. other other with combination in used is Sitagliptin when also patients is required when filing an application of application an filing when required is patients on opinions advisors’ feasibility - cross tobe as so be developed should plan surveillance , group control include a PMDA ; programs surveillance patients is not higher than that in foreign patients by comparing incidence comparing by patients that in foreign than not is patients higher is overseas and Japan between on Based e whether there there are whether
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page109
). as he .
the the the
days pooled n these
and and I ) ), ) % Sitagliptin Sitagliptin Sitagliptin Sitagliptin 801 ( (
. years for years
-
] ] ] ] ] cardiovascular cardiovascular 3
, 0. 0.5 CI 0.2 1.1 ; the duration of ;of the duration
- - shown in the inas shown , the , , , 0.3 0.2 0.4 0.1 - - - 0.9, 1.0 1.0 1.0
95% - - patient In these studies, t studies, these In - - [ twice daily twice [ [
days [ [ /day . exposed groups marketing surveillance marketing - - assessing cardiovascular cardiovascular assessing 307 . not been, has performed 2270 non
) ****************** post 50 mg mg 50 The corresponding numbers numbers corresponding The 100 mg 100 for
patients with type 2 diabetes diabetes 2 type with patients
Difference between Sitagliptinand agent
patients in the Sitagliptin group group the Sitagliptin in patients of this guidance
* years group group Sitagliptin the een
ccount of the comments from the the from comments the of ccount . years 2 1343 betw , , respectively 290, including cardiovascular risk cardiovascular including as cardiac disorders as
(
) that was treated concurrently over almost over concurrently treated was that taking a
and antidiabetic
a particular risk of cardiovascular events in in events of risk cardiovascular a particular % % % % days; the duration of treatment, 1- treatment, of duration the days; exposed group 2724
-
events and of the 6139 =
1.5 2.3 1.5 3.9
n agliptin (
novel novel As a result As
the Sitagliptin group and 100 or once daily mg a
referenced to overseas to referenced
( weeks 109 . However, for for about , about cases , ****** Sitagliptin non patients received placebo or active control or active placebo received patients 106 . pooled the mean duration of treatment, treatment, duration of mean the ( group group
to years years - patients were treated for for treated were patients
were were group
- cross tobe /day )
356 study ****
% % % % ( 3415 studies included in this analysis were not cardiovascular outcome outcome cardiovascular not were analysis this in included studies
exposed group were 981 were group exposed 100 mg
= -
1.2 2.0 1.1 4.0 so as as so group control concurrent the n ( ( 100 mg 100 he
ofwhich Sitagliptin in eachin study ,
and the other 2724 the other and ) ) Though t Though Table. Incidence of adverse events categorized events adverse of Table. Incidence year at least 3 years of observation period are needed needed are period observation of years 3 least at
1
, as follows: as )
days ardiac ardiac studies evaluating the safety and efficacy of Sitagliptin efficacy and the safety evaluating studies . performed was clinical and phase of Sitagliptin studies III phase II foreign . ≥ currently required by the required FDA by currently ed events of exposed group
patients received Sitagliptin received patients SOC ( ere ere
as the mean duration of treatment, 294 treatment, of duration mean ) (the group 792
riod time of 1- in order to assess the overall safety of Sit safety overall the toassess inorder ed 3415 , he duration of treatment was 18 was treatment of duration he , ischemic events ischemic events disorders cardiac disorders Adverse events of expos . exposed group exposed group, indicating that the risk of cardiovascular events is almost comparable between between comparable almost is events cardiovascular of risk the that indicating group, exposed Serious adverse events of Serious adverse Adverse events of c llitus s Sitagliptin was approved about 2 years prior to the enforcement tothe prior years 2 about approved was s Sitagliptin did indicate did not studies 12 foreign from data pooled he ) 2008 December However PMDA consider T Discussion Expert study *********************** type 2 diabetic patients treated with Sitagliptin with treated patients diabetic 2 type events andtumor development The applicant responded as follows: as responded The applicant A ( risk analysis, analysis, risk 12 from analysis , t studies me were treated for for treated were treatment, treatment, non- The data from the Sitagliptin the from data The Sitagliptin non- Sitagliptin the same pe the same of patients in the Sitagliptin non Sitagliptin the in patients of 2994 patient was period total observation non- studies, but w studies, but table below, there were no meaningful differences in the incidence of adverse events categorized events of adverse the incidence in differences no meaningful were there below, table ischemic of events adverse including disorders cardiac non- Sitagliptin with untreated those and Sitagliptin with treated patients diabetic 2 type
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page110
l a o
be and fied The drug via
also capable patients and it is overseas fied on will etc. etc.
) r events and and r events attempting to to attempting with cardiovascular cardiovascular (scheduled for for (scheduled , ************ . examined
by of he duration of this this of heduration the mentioned speci **** - and and information information
study setting Although t Although studyis patients with moderate renal withpatients renal moderate **** results survey of patients with with patients of survey results
- marketing surveillance protoc surveillance marketing in and then explained and then as follows: direct comparison , direct - ) use
**** moderate renal insufficiency can be be can insufficiency renal moderate
practice and procedures and practice draft fied but also by also but ( with information on cardiovascula information collected via thecollected via above ocol Sitagliptin In the theIn end, in to collected cases addition ***********
. actively collect safety collect actively
marketing surveillance protocol (draft) (draft) protocol surveillance marketing cases are expected to be collected be to expected are cases of
-
** results survey of patients with renal insufficiency insufficiency renal with of patients survey results When
- ompletion of the survey period once the the period once survey the of the completion before due to different 110
the data collected from randomized controlled clinical clinical controlled randomized from collected data the use when done when can be
about about term treatment with Sitagliptin will be collected collected be will Sitagliptin with treatment term boratory data etc. will be re data will etc. boratory la relevant with term use and a speci and use term fied
- , dose adjustment, it is necessary to conduct a speci a toconduct necessary is it adjustment, dose promptly promptly , events cardiovascular efficacy, safety, on information he T is difficult is
speci type 2 diabetes mellitus mellitus 2 diabetes type year observation period and a planned number of cases of 3000. of cases of number planned a period and observation year
term use ( use term a 3- -
, etc. collected , events all adverse collecting , safety, and efficacy and safety, ,
marketing surveillance prot surveillance marketing * ************ - nts with with nts use by survey results with a a with
. in order to collect information on patients with moderate renal insufficiency insufficiency renal moderate with on patients information collect to order in drug including the primary endpoint of endpoint primary the including
, , and ************************ ***************** patients with renal insufficiency to insufficiency renal with patients . ***********************
. that there are no major problems with the post the with problems major no are there that s , asked the applicant to present a post a present to applicant the asked
e , years results survey on the long results survey lthough patie lthough - the above assessment of survey results on cardiovascular events on cardiovascular results of survey assessment study will be collected via collected be will results survey survey results -
use
PMDA and a use results survey on the results long survey , year observation period and a planned number of cases of 100. of cases of number aplanned and period observation year
- concluded **** fied e - a long following etc. development
1- . However, not. However, only s
. . the response accepted ) and fied programs surveillance marketing - results survey of survey results this survey, patients with moderate renal insufficiency renal moderate patients with thissurvey, -
th moderate renal insufficiency renal th moderate draft studie also difficult to compare the tocompare also difficult a with ( information on actual on information insufficiency included in analys has been has development tumor us drug PMDA , assessments similar perform 20**) survey items items as survey events , **************** careful administration and and administration careful by managed wi tumor speci survey will be 3 a post presented applicant The speci A Therefore, summarized be will results survey early, collected been have of cases number the target data from programs use of investigating via With respect to respect With post renal insufficiency will conducted. be renal insufficiency
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page111
, the effect is is the effect
If of the following of the following
to any one any to once daily.
examination period is 8 years, is 8 years, period examination - ed r e exercise therapy exercise exercise therapy exercise administ exercise therapy therapy exercise
/or
orally orally
py and/or therapy and/or therapy 111 thera redient, the appropriate re appropriate the redient, itagliptin itagliptin concluded that the product may be approved after modifying modifying after be approved may product the that concluded
PMDA 50 mg of S 50 mg in to addition dietary
s exercise therapy only therapy exercise
in to addition dietary s /or in addition to dietary therapyto dietary in addition and
s dosage is dosage
Overall Evaluation Evaluation Overall
he usual adult usual he
Indication] insufficient, the dosage may be increased up to 100 mg once daily while closely observing the clinical clinical the observing while once closely daily 100 mg up to be increased may dosage the insufficient, course. T (b) Use of sulfonylurea of (b) Use [ mellitus; diabetes 2 Type respond sufficiently do not who in patients only be used should Sitagliptin III. review, above the of result a As the indication and the dosage and administration as shown below. As the product submitted for for submitted product the As below. shown as andadministration the dosage and the indication ing active a new with a drug is registration
treatments. therapy Dietary (a) and (c) Use of thiazolidinedione of (c) Use either the drug substance nor the drug product is classified as a poisonous drug or a powerful drug a powerful or drug poisonous a as classified is product drug the nor substance drug the neither product. biological or a specified product a biological as classified not is product and the and[Dosage administration] (d) Use of biguanide of (d) Use
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page112
, e
. . . . . m rug um D starting starting the residue on
, size , particle ding levels of of levels mass spectrometry, spectrometry, mass properties have been been have properties
, ) by ultraviolet spectr ultraviolet by cess is ************
C 13 , water content, content, water , Glactiv Tablets 25 mg, 50 50 25 mg, Tablets Glactiv ) ]
and HPLC proton, proton, (
characterized um 100 mg its physiochemical its (IR) identification scription,
and
The manufacturing pro The manufacturing
112 related substances [ substances related
solubility, optical rotation, crystalline polymorphism, polymorphism, crystalline rotation, optical solubility, ray diffraction ray
- have been set for de set been have review by PMDA regar PMDA by and outline the of review , and dissociation constant. dissociation , and Puerto Rico). Rico). Puerto
ck Co., & Inc. crystal X crystal Concerning related substances, specifications for for specifications substances, related Concerning [HPLC]), purity ( purity [HPLC]),
. Sitagliptin Phosphate Hydrate Phosphate Sitagliptin Hydrate Phosphate Sitagliptin Mer 220MF10082 Januvia Tablets 25 mg, 50 mg, and mg, 50 25 Tablets Januvia , nuclear magnetic resonance spectr resonance magnetic nuclear ,
Merck Sharp & Doh & Sharp Merck by is manufactured Hydrate, Phosphate Sitagliptin a white powder and its structure has been been has structure its and powder a white
(HPLC)
(IR) ]
******************************************************************* enantiomer
) 220MF10082 - ) S um ( (
(DMF) for(DMF)
) me] ile o.] ummary of the submitted data submitted the of ummary proprietary name] proprietary s -
ppendix MF N aster F aster substance, drug he D Name of submitter Name infrared spectr infrared - single and analysis, elementary
substance is The drug ********************************************************************************** ********************************************************************************* *************** . ********************************************************************************** ******************************* ************************************************** ********************************************************************************** ********************************************************************************** ********************************************************************************* ********************************************************************************** *********** *********************************************************************** ********************************************************************************* ********************************************************************************** * ******************************************************************************** the drug substance to the pertaining data Summary the submitted of T ( Ltd. Rico Puerto de Quimica ****************************************************************** **************** ********************************************************************************** (A The ( mg mg, and 100 na [Brand The specifications for the drug substance substance for the drug The specifications purity optical [ [Non [ ignition, and assay and assay ignition, determined by description, thermal analysis, thermalanalysis, description, by determined pH coefficient, partition hygroscopicity, M
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page113
, ) ) 2
lot
acid was
) l h/m , and , and · under under ) were . As a oxidative oxidative lots ********* ********* degradation ], 4 months, months, (HPLC) (IR) and color(IR) of acid hydrolysis 36
. Likewise, related related . Likewise, , degradation product product degradation al degradation months, 3 lots36 months, degradation product degradation months, months, and heavy metals. heavy and tests as a result, result, a as
but these degradation degradation these but
********* hydrolysis, hydrolysis,
%RH 6
RH, the total leveltotal the of related therm , (HPLC) degradation product was was product degradation , and assay , and /65 ) ne
%
C
° al and /60 , arsenic, ********* %RH C 5 identified, identified, ]) ************************ /7 dentification dentification i [ C *************************** 0° hydrolysis and hydrolysis and
were (4 ,
ne
determined, determined, *************************** , and ********* , and , ************************************* performed and the tested attributes performed were (30 testing term far. so produced ) s
validation, stress testing ( testing stress validation, term testing (25° testing term
lot al degradation related substances substances related
113
degradation test period for the drug substance is 36 months when when is 36 months substance drug test the for period optical rotation optical phosphate, al hydrolysis [ hydrolysis
], therm the attribute tested was assay was tested attribute the total level of related substances of related level total , but therm , but degradation ve ve degradation the individual individual tances (HPLC) ( (HPLC) tances degradation product alkali after product degradation months, l , 6 months, s , accelerated testing , accelerated after acid and alkali and acid after
)
placed in fiber drums at room temperature. temperature. at room drums fiber in placed and ne alkali in photostability testing. testing. in photostability assay method assay lots other
5%RH 3 /7 nd C a after oxidati after identified ********* (40° cool white fluorescent lamp white lamp anand of near cool fluorescent illumination ultraviolet lamp, overall months, months, samples (pilot scale) stored in double polyethylene bags placed in fiber drums. The The drums. in fiber placed bags polyethylene double in stored scale) (pilot samples and samples after samples and degradation and oxidative hydrolysis, enantiomer [HPLC]), and assay (HPLC) assay and [HPLC]), enantiomer term, accelerated, and photostability testings, the samples met the specifications for for specifications the met the samples testings, photostability and accelerated, term, - - ) ne 36 related substances substances related ******* *************** ************************************ *************** ******* g S , HPLC) were determined for samples after samples for determined were HPLC) ************************ [ were also performed performed also were the drug substance has also also has substance drug the specifications, the in included not Though provided. been have have never been found in the drug substance drug the in found been never have
stability studies of the drug substance, long- substance, thedrug of studies stability /60%RH C the ) after therm ) after *********************** ], ************************ photostability testing ( testing photostability of not 200 W less than energy ultraviolet near integrated ·h and an lux thannot 1.2 million less identified identified product was and accelerated testing and accelerated products substances substances of , identity solvents been tested for residual the solution solution the (25° also performed on 1 pilot scale and lot 1 pilot on alsoperformed degradation product after oxidati after product degradation ( - re the proposed results, above the on Based degradation product was was product degradation were substances related When . ******************* hydrolysis, acid after stored in bags double polyethylene degradation degradation ( substances and performed was assay testing, thestress In assay. for as condition thesame individual other individual of part as Furthermore, [ description, water content, related sub water related description, content, - long scale, a commercial at lots produced the Using alkali hydrolysis, As materials ********************* d on performe were (( purity optical attributes tested in these studies include description, water content, total related substances (HPLC) substances related total content, water description, include studies these in tested attributes result, in the lon the in result, all attributes and there were no quality changes. changes. no quality there were and allattributes
ジェノトロピン 2.6.2.5 薬力学的薬物相互作用試験 Page114
, is to to
about about liptin, liptin,
and no than the
registrant adjacentto the severer
MF , when the drug drug the when , s to explain to
wa the
the asymmetric carbon carbon asymmetric the the manufacturing process the manufacturing
stable and racemization stable drug in thebe included will drug conditions
********************* instructed during
from
carbonyl and is group carbonyl thedry [HPLC])
PMDA the , as Sitag , ******************** MF registrant MF the asked is introduced
enantiomer, optical purity is increased. Based on on Based increased. is purity optical enantiomer, enantiomer -
in accelerated testing, which which testing, accelerated in -
)
S) S ( 114 ( c carbon of Sitagliptin is of Sitagliptin c carbon chirality 5%RH aromatic ring and ring aromatic /7 the
C s with specification the problems no particular there are that
the 40° of the drug substance in substance drug the of is very important. Thus, ), all 4 lots were stable stable were lots 4 all ), ***************************
In crystallization of of crystallization In
concluded position to position
in *********** all lots in reduced β
asymmetric carbon, PMDA carbon, asymmetric . the stability stability the by PMDA s the stable against racemization. Racemization is likely to occur in tooccur likely is Racemization racemization. against stable
determination in
responded that optical purity ( purity optical that responded drying process ( is , taking into account that into , taking has been has , there should be no racemization or decreased decreased or racemization no be should there , ***************************** test period established for the drug substance. substance. drug the for established test period - re Concerning
registrant registrant registrant explained as follows: as explained registrant t is located t is located and lthough the asymmetri although that considers
tha MF enantiomer, is thermodynamically superior to enantiomer, is thermodynamically enantiomer enantiomer , optical purity optical , - - ) R S) specifications. specifications. substance drug final in the purity optical include The etc. unlikely tounlikely occur PMDA the above, Based on
the in above, chirality. PMDA racemization was observed. Moreover, also in terms of chemical structure, structure, chemical of terms in also Moreover, observed. was racemization atom . ************************* ( storage, ( *******. the condition of As Sitagliptin has an has Sitagliptin As The MF Outline of the review
racemization and a decrease in chirality during the manufacture of the drug substance. drug the of manufacture the during in chirality a decrease and racemization substance was stored for 6 months at months 6 for stored was substance group amino substance specification substance response. the PMDA accepted