Science, 0(ja).https://doi.org/10.1111/cts.12671 of CYP1A2and inductionofCYP2A6by theantiretroviraldrugefavirenz inhealthyvolunteers. ClinicalandTranslational Metzger, I.F., Dave,N.,Kreutz,Y.,Lu, J.B.L.,Galinsky,R.E., & Desta,Z.(n.d.).CYP2B6 genotype-dependentinhibition This istheauthor'smanuscript ofthearticlepublishedinfinaleditedformas: [email protected] Phone: E-mail: 317-274-2823; 317-278-2765; Fax: and Indianapoli R2 425 Indiana Division Zeruesenay Zeruesenay author: #corresponding Galinsky MetzgerIngrid F. Running title: in healthy drug efavirenz by volunteers the antiretroviral ofCYP2B6genotype-dependent inhibition CYP1A2 of induction CYP2A6 and b Medicine, of Indiana,School USAIndianapolis, a § *
Present address: Blueprint Medicines, 45 Medicines, BlueprintSidney Street address: Present Division of Clinical Pharmacology,Divisionof Medicine,Indiana of Department University School of of Pharmacy,School University, Purdue Lafayette, Indiana, USA West Accepted workcontributed this andN.D I.F.M to equally Article 950 West , 950 Walnu West Un o a ,b f Clinical Pharmacology f , Zeruesenay, Desta s, IN46202 iversity De Efavirenz alters sta a * , PhD S , Nimita Dave Nimita , chool o chool t Avenue Medicine f Medicine a# in vivo in
a, , Departmen * § , Yvonne Kreutz CYP1A2 CYP2A6 and t of ,
Me a dicine dicine , Jessica B.L. B.L. Jessica , , Cambridge,MA 02139 Lu a
, Raymond E., This article isprotected rights by All copyright. reserved. Accepted CYP2A6activity.noted for singleand following of doses efavirenz.multiple was both association similar No unaffected. CYP2A6 increased efavirenz and spectrometry. and wereplasma liquidurine using quantified with treatment mg/day 600 17 days. efavirenz metabolites for and its Caffeine in on two58) separate occasions; oral single150mg A doseofcaffeine was to(n healthy administered volunteers oxidase N xanthine (XO) and investigated theeffectWe of efavirenz Abstract Article N caffeine, Keywords: University grant (PHS were atthe CTSI performed clinical studies Medical Sciences/National Health InstituteGeneral MD). of (NIH) (Bethesda, The R01GM078501, Funding: Conflict of Interest. CYP2B6*18 (983T>C)
treatment, multiple treatment, This project Service bywasThis Public Health supported (PHS) grant - acetyltransferase 2,acetyltransferase xanthine oxidase CYP2B6* efav
DNA was genotyped for irenz, R01GM121707 (by 85%) The authors declared The no 6*6 UL1TR001108, CYP2B6
genotype wasgenotype associated with lower
This is the first This alleles - - doses ofefavirenz CYP1A2 decreased activities( acetyltransferase (NAT2), 2 a using caffeine as probe.
genotype, drug with single a mg o 600 and
using TaqManassays. T32
NIH). CYP2B6*4 (785A>G), on the CYP1A2, activities the CYP2A6, of on P GM008425 from the
< 0.05); < 0.05); report
Clinical Research Center Indiana Clinical Research of
chromatography/tandem competing interests competing for work. this - drug interaction, CYP1A2, CYP2A6, drug interaction, showing efavirenz that
XOand NAT2 activitieswere
ral dose ral dose of efavirenz R elative to single CYP2B6*9 National InstituteNational of CYP1A2 activityCYP1A2 (by 38%) - mass reduces reduces (516G ; -
dose dose and after after and
a >T)
nd = , This article isprotected rights by All copyright. reserved. metabolism) Accepted of administration of transcription drug (CAR) drugdispositionviainduce of genes activation toand manage DDIsiscrucial predict them. these drugs those they as concerns pharmacokinetic of use first to recommendefavirenzcontinues integrasesuchnewer inhibitors as agents Article alternativeconsidered therapy infected thepreferred been first withcombination two Introduc dependent. efavirenz CYP2A6elimination is alsoof substrates. This to the reportthe offirst extent CYP1A2 hepatic and suggesting efavirenz likelythe chronic exposure enhances - line therapyline Most non The efavirenz (6) adults tion -
CYP1A2 interaction interaction CYP1A2 and pregnane X (PXR)and receptor
efavirenz mediated co (9)
- - (1) administered , nucleoside HIV
(6) is associated is associated in resource in
drug e potentially increas
favirenz increases its favirenz own increases elimination and
and those of others through and those others ofof drug metabolizing induction - metabolizing enzymes and transportersmetabolizing and enzymes nucleoside/ - drug interactions (DDIs)drug interactions - children children line regimen regimen line -
limited countriesHIV with pandemic with may be may be with often and unpredictable numerous since since 2015 - (2) 1 reverse transcriptase inhibitor efavirenz inhibitor reversetranscriptase 1 DDIscan be explained by efavirenz’s to ability nucleotide efavirenz . - based therapies as cost therapiesas based Although e for over 15 years over 15 for
the risk for loss of loss efficacythe riskfor ofeffects adverse or efavirenz exposure
(3) due to due to the increased effectiveness of (7) .
reverse Thus , the , the regimens containingregimens efavirenz are , nuclear receptorsthatnuclear constitutivethe androstane receptor (5) , . These DDIs These are .
World Health Organization World
understanding themechanisms of
transcriptase inhibitors, transcriptase for treatment for naive HIV (“ - autoinduction” of autoinduction” of
and - effective convenient and (8) CYP2B6 . As As . result a (4) of of .
However, the regulate regulate major clinical
genotype ,
i n , has
chronic the - This article isprotected rights by All copyright. reserved. influenced by HIV in patients dosing ( CYP2A6.efavirenz CYP1A2 and on vivo induction). to testthe appropriate of efavirenzeffect on inhibition of ofprediction a thisDDIpotential drug candidate, approach wouldnot be While that (HLMs) liverand/or preparations expr microsomal it making slow acetylators whothose efavirenz inare acetyla 29%) (by fast predicted isoniazidmodel exposure of exposure was (NAT acetyltransferase 2 2), enzymes, potential ef the in reduction elimination of concentrations showefavirenzcertain enzymes that inhibits directly DDIswith to due induction of drug efavirenzare dispositio enzymes including CYP2B6*
Accepted Articleavirenz
efavirenz CYP1A2not theactivities inhibit/inactivate does of studies probe using substrates HLMs are Efavirenz byCYP2B6 metabolized hepatic ismainly in vivoin difficult to attribute the observed effectto efavirenz alone. being being such such 6 A
and ppropriate CYP2B6 (e.g.,
as CYP1A2 as a mixed inhibitor/inducer of inhibitor/inducer mixed CYP2B6 a effect efavirenz of activity the other on of CYP2B6*18 (17) important CYP2B6, CYP2C19 and CYP3A . However, these However,. these CYP2B6,CYP2C8, CYP2C19 CYP2C9 and (19) genetic variantsgenetic in vitro in . in vitro , The The extent e of
CYP2A6 ) produce ) produce efavirenzhigher standard after exposure is not fully investigated.
CYP2C8 and CYP2C9substr models (e.g.,human cell or models hep lines experimental are required to required exclude are the potential effect of
,
patients weremedications receiving multiple xanthine (XO) oxidase N and (20) favirenz is ofmetabolism autoinduction . gene gene (e.g., expression due to enzyme Recent evidence Recent tools tools tors essed enzymes,have shownessed we
, but but , (10) (16) at therapeutically at relevant In HIV/TB to to marginally estimate estimate ,
(11) no effect observed was in and CYP2C19 drug metabolizing n genes. Our (18) ates , (12) indicate - . Two gene variants co reduced by reduced in vivo , the ) .
CYP2A6 - (13) infected infected patients, However, not all However, not - atocytes) or atocytes) or Using estimation and and estimation ,
that the
in vitro in (14) (11) with human human (13) , . (15) The The
data data . in
and , This article isprotected rights by All copyright. reserved. Accepted (600 mg/day) occasions: metabolit in wereNAT2 profiled healthy using and urinary and volunteers caffeine plasma drug interactions CYP2A6, CYP1A2, XOand NAT2 epidemiological drug activitiespopulation, in and ratios metabolic whichpathways make to clearance validate difficult oral ofagainst caffeine, caffeine metabolites (NAT2).acetyltransferase 2 efavirenz CYP2A6, theactivitiesxanthineof on (XO) oxidase N and CYP1A2. for paraxanthine Article in iselimination humans via mediated hepatic CYP1A2 administrationcaffeine in metabolized humans least identified with17 metabolites in at the urine followin correlated with variation in genetic CYP1A2 in activity healthy of volunteers magnitude and (2)the of the alteration variants other maydeterminantand be important of the magnitudeoffactors DDIs. variablesuggesting efavirenz to that functionally exposure relevant levonogestreland of efavirenzextent The main studyThe objectives ofthis main (1) efavirenz weretest whether to es as as es an with The seco The (26) treatment for 17 days. treatment for
a single600 a doseof mg oral chronicefavirenz after efavirenz and of (27) ,
(25) in vivo - (22) caffeine caffeine mediated DDIs with such DDIswith mediated as such CYP3A lumefantrine substrates
(24) , (24)
ndary objective of ndary of this objective study isto
and caffeine is welland a also depends thevariability also on in (23) ,
(25) probe , (25)
, have been widelyhave been convenient as used markersof (24) CYP2A6, XOand N . Although these. metabolic enzymes catalyze minor . s offollowingcaffeine administration on two the Activities of hepatic CYP1A2,CYP2A6,Activities hepatic XOof and , (25) CYP2B6 CYP2B6
. Approximately to 90% of the caffeine total 80 - expression established and validated and established drug probe AT2
are involved in the involvedare formation the of in - . mediated demmediated explorethe of effect Caffeine is Caffeine extensively CYP2B6
gene expression CYP2B6 - ethylation to
alters the the alters urinary
genetic genetic (21) g ,
-
This article isprotected rights by All copyright. reserved. Accepted drug interactions: later, NJ)Myers Princeton, withwater mLon Squibb, 240 received a participant each single600 thehospital anto ~7overnight AM, sample, after fast. Followingblood predose a withday treatment efavirenz mg 600 daily. singleconcomitantly a with mg oral 600 dose efavirenz of the end again at of 17 and received volunteers determine efavirenz pharmacogeneticsefavirenz druginteractions and autoinduction, Study design. NCT00668395).number consent. atClinical Researchconducted theIU Center.gave Allparticipants informed written Article ReviewUniversity approved (IU) thepro Board Institutional subject DNA genotyping toeach extractfor genomic purposes. (11) inclusionand of exclusion criteriaareprevious in described our physical clinical history examination, medical standard laboratory and tests. into enrollment study) to prior the for underwent a 20 BMI, Study subjects. ANDMATERIALS METHODS , (28) a cocktaila probe drugs - 32 kg/m
, The study atThe registered was (29) pre , (30) This study This twoa used - 2 enrollmentscreening Healthy male and Healthy female male ) were recruitedto participate this in study. . 150 mg caffeine During screening,a the - a probe twowatercocktail withdrugs on orally occasions: mediated changes in drug hepatic me mediated
was
administered orally assess potential water to with administered , 2 50 tolbutamide, mg 20 omeprazole, mg 1 and any medical a - http://www.clinicaltrials.gov - session design sequential to characterize examination (within six maximum of a weeks mg oral dose mg oralof dose efavirenz (Sustiva
On day 1, the day 1, participantsOn were admitted volunteers (age,18 to and 49 years old; blood sample( bnormalities,which included
an empty stomach tabolizing tocol and thestudy was 10 ml) was obtained obtained was from ml) 10 Potential The The Indiana publications
(ClinicalTrials.gov ( Figure enzyme enzyme
subjects . One hour S1 , Bristol ,
Details Details ) . To . To activity, - - This article isprotected rights by All copyright. reserved. . ofCYP1A2,NAT2 CYP2A6, marker XO. and here thedata present relatethat to efavirenz with as caffeine metabolism interaction day in as 1 efavirenz oral later,one hour mg) and (600 pre After the hospital. tofrom day day 7 23. the ofdayOn morning were 24, participants again to admitted analysis. Plasma recorded. and samples urine were aliquots urine saved pointfrom each time after the total centrifugation 20 minfor at inPlasma was efavirenz was collected byfractions. separated administration 48, 72 hours and 144 outpatients.as hours following whilewere and thehospital participants in at efavirenzadministration an indwellingcollected 1, 0.5,2, 1.5, 2.5,from 4, catheter 6,3, 8, 10,12, 24 16 and cocktails. phenotyping CYP several in validated been co the of components other the among (or omeprazole and caffeine of interaction is no there fact, In activity. CYP1A2 alter to expected not is study this in used mg) (20 dose single small the administration, chronic after syrupmg of midazolam
Accepted Article here) used cktail The volunteers The chronic oral began efavirenzthe evening, mg/day)in (600 . All other proceduresAll other .
for simultaneous use without fear of interaction interaction of fear without use simultaneous for
and these these and - dose collection, blood receiveddose their participants dose of final . Although high doses of omeprazole can in can omeprazole of doses high Although 3,000 rpm 3,000 probe drugs (including caffeine and omeprazole) omeprazole) and caffeine (including drugs probe and sample processing All urin were within collectionan of hour and two 10 Venous blood samples (10 samples (10 blood mL) wereVenous
immediately stored immediately at stored a a probe cocktail drugs e voided duringafter voided e the24 hour
mutual mutual were to identical day 1. urine volume is urine volume pharmacokinetic pharmacokinetic and – was administered was 80 duce CYP1A2 CYP1A2 duce thus widely used used widely thus o C until C until - ml ml have have W e
This article isprotected rights by All copyright. reserved. were slightly used different”. were separatelysamples run thenumber analytes as of tested and the methods singleand samples were doses together. from multiple run singleand were doses run.from multiple Similarly, assayed the same in urine Me previouslyhave been published the in metabolizer ( ( instructions Foster Biosystems, (Applied Discrimination Kits City, thesupplier's to CA) according were I328T) using(983T>C, genotyped Assay TaqMan Q172H) PCRtime instruments reaction chain Polymerase (PCR) was on performed theQuant Studio12K Flex real wholewas from ( blood extracted functional population occurs and relevance high at ethnicallyfrequency across the ( The DNAgenotyping. Accepted *1/*1 Articlehttps://www.pharmvar.org/gene/CYP2B6 asurement of drugs and metabolites and asurement ofdrugs in urine. and plasma CYP2B6*4 CYP2B6 CYP2B6 genotype,n=36), intermediate ; CYP2B6*4, (785A> rs2279343
protein s .
(19) Genotype the analysis considered groups for were norm *6/*6* gene is gene highly polymorphic,
and gene other and . In addition, the is
genotype CYP2B6*9 frequent in population black frequent
blocks for blocks 96 for
, n=
variantson the haplotype, same CYP (28) 5 and and 5 CYP2B6*18 QIAamp DNA Min -
well plates , variantswere genotypedthat in samples these (30) metabolizer *1/*18 G, G, K262R);and CYP2B6*18, rs28399499 . ). T
with alleles over reported 38 to date
he
allele allele genotype, genotype, n=1) . CYP2B6*9,. CY2B6*6 (4 ( *1/*6 *1/*6 - i Kit, i Kit, 12%) whichexpressdoes not
- genotype, genotype, n=15) andslow Reagent Allelic Reagent Qiagen, Valencia, CA). Qiagen,Valencia, (19)
and geographicallyand diverse allele, which
Plasma and Plasma urine and rs3745274 (516G>T,rs3745274 . .
The additional additional The Briefly, has functional
“Plasma samples al metabolizeral genomic consists of consists of variants
DNA
- This article isprotected rights by All copyright. reserved. separation chromatographic MD). was The Columbia, achieved using Restek C8 a UFLC auto spray source. ion Th (Appliedspectrometer Sciex, with City,Biosystem/MDS a Foster turbo CA) equipped its and Caffeine chromatography/tandem A reconstituted in and 120 µL of phase50% mobile A and 50% B. phase mobile Coulter,Schaumburg, (Beckman layer organic toIL). wasdryness The evaporated 10mixture shaken for min 0.1M) standards internal andthesample vortexas efavirof incubated at18 and hours to 37°C for hydrolyze conjugates circulating glucuronide 600mM(pH=5), sodium of 12.5µL azide and ofβ 25µL metabolites. of extraction Plasma quantification and commercially available. chemicals andAll other were solvents the HPLC highest or grade quality were York, Ontario, (North Researchfrom Toronto Chemicals purchased Canada). hydroxyefavirenz,8,14 theophylline were (AFMU),and MU),1,7 Chemicals.
Acceptedliquot Article and 6 (25 µL) (25 enz. - dimethyluric acid - sampler, DGU
Caffeine (1,3,7 TMX), mL ofethyl (50/50,v/v) acetate/hexane was and thesample added E
1,7 Plasma ( Plasma favirenz was the onto injected metabolites weremetabolites on an API quantified 3200 triple - dimethylxanthine (1,7dimethylxanthine DMX) orparaxanthine and theobromine and purchased Sigma purchased from e consist system twoHPLC of LC - 250 µL 250 - d4 dihydroxyefavirenz,7
- mass spectrometry ( -
(30µL (30µL of 1µg/mL) and then 20A3 degasser CBM 20A3 and a ( 1,7 DMU), )
was with mixed µl 250 sodiumof acetate0.2M 1 - centrifuged at3600 10min at rpm 0°C for methylxanthine high performan
5 - acetylamino - AldrichLouis, MO). (St. Efavirenz,8 efavirenz,
and 1 mixed - hydroxyefavirenz, β and HPLC
µg/ml µg/ml wereacetaminophen added . - H
ce liquidce MS/MS - (1 MX), 6 ydrochloric acid caffeine - - - - 20A controller (Shimadzu, 20AD 20AD pumps,SIL glucuronidase (1000U/mL) formylamino ) 1 system. -
methyluric acid and and the - quadrupole mass quadrupole mass - 3
- - (250µL (250µL of glucuronidase glucuronidase methyluracil ir respectiveir - 20AHT -
( 1
This article isprotected rights by All copyright. reserved. hydroxyefavirenz,7 measure first and third transitions (Q1/Q3) quadrupole efavirenz, 8 for 329.98/210.0, in detailed our previousas publication byquantified LC/MS/MS E intraconcentrations. The over was and ng/ml a all analytes linear for using wereAnalyst performed Data were paraxanthine acquisition separated. chromatographically processing and standard), respecti (internal 152.13/110.20 and theophylline,for caffeine, paraxanthine, and acetaminophen Monitoring Reaction standards internal the were as previouslydescribed optimized 60 of time positive unit mode under resolution quadrupolefor 1 positiveThe mode. analytes source werea at temperature optimized of 400°C in theophylline, caffeine, paraxanthine of both adjustment the com gradient describedelution a elsewhere in acid [methanol : B (0.1% water formic phase [methanolMobile A : formic acid thesamplinginjection, was acetonitrile/waterneedle with washed v/v). (75%/25%, 5µm (Bellefonte,(250X4.6mm, particlesize) P column
Acceptedfavirenz,8 Article
ms and and settingms a of time 700 - hydroxyefavirenz,7 329.98/257.89, 345.91/262.0, 318.01/247.95 wasand to used - hydroxyefavirenz,8,14 (MRM) - in negativein using mode day and inter day and pound vely, waspositive used. in mode at at ® m/z
software. - hydroxyefavirenz and 8,14 hydroxyefavirenz and -
and instrument of 195.12/138.12,181.13/124.20, 181.13/124.2,of and (30) -
(30) day variabilities wereday 20%. variabilities than less ms. Gas pressures all analytesfor (0.1% waterin ; acetaminophen acetaminophen 99/1,was v/v)] pumped The lower limit of quantification was quantification lower 1 The of limit . - . MS was optimization achieved via wide range therapeuticallyof relevant MRM dihydroxyefavirenz, efavirenzand efavirenz at at - dependentparameters for m/z
and 3, givenand were dwell a ; A). BeforeA). each after and
1/99, v/v)] 1/99, mobile phase and of 313.97/244.01, of ( internal standardinternal - d4 as an internal standard internal an as d4 -
dihydroxyefavirenz Theophylline and (30)
at 0.8 using ml/min . Multiple Multiple . - , )
including including
in
- d4 were
This article isprotected rights by All copyright. reserved. were separated peaks chromatographically. transitions, (Q1/Q3) acetaminop 225/197 for for fo methanolpH=3.5)/90% (v/v) pH=3.5)/1% methanol (v/v) of0.5 rate and cons mL/min Technologies, Zorbaxseparated on a XDB Eclipse onto wasLC/MS/MS describedsystem injected above plasma. wereAnalytes for =pH (20mM, 4.8) Residue vacuum. speed was in reconstituted µL 100 of acetate99% ammonium layeraqueous layer by theorganic wasand evaporated suction using decanted vortex(85:15), ofacetic ac µL standard (nevirapine,500ng/mL).internal Each was sample extracted 300 by adding and extraction Urine quantification. hydroxyefavirenz) chromatographically.were separated standard), respectively,(internal negativ in
Acceptedr theophylline, paraxanthine,181.13/124.2 for 181/138 theobromine,166/149for Article 1 - methylxanthine hen (internal standard) 5 - acetylamino - id (0.1%id water) of in 6mL and Santa Clara,Santa CA mix for centrifuged 20s, at 3600 5 for mix rpm minutes at for 10°C. The /1% andvortexmethanol in positiveTheophylline,paraxanthine mode. and theobromine , 183/105 - 6 ] ist - ]. and phase B phase and formylamino MRM at at MRM
1 of of ) - . T methyluric acid, phase A he gradient was used and to measure thirdfirst quadrupole - C8 column (4.6 xcolumn C8 Agilent 150mm, 3.5µM, Urine (250 was µL) 30µL with spiked of m/z
- [
3 10% acetateammonium (20mM,
[ e mode. mode. e - 195.12/138.12 for caffeine, 181.13/124.2for 195.12/138.12 99% acetateammonium (20mM, - mix for 15 seconds. 15 An aliquotmix(50µL) for methyluracil
dichloromethane: isopropyl mobile phase mobile
195/180 Metabolites (8
(AFMU) and (AFMU) and
for for
was ata pumped flow 1,7 - dimethyluric acid, dimethyluric acid, - and 7 152.1/110.2 152.1/110.2 for
- alcohol alcohol This article isprotected rights by All copyright. reserved. caffeine. respective enzyme activity estimation pharmacokinetic parameters of of besides following p of useful are CYP2A6,markers CYP1A2, XOand NAT2 activities validated ratios S of metabolicratios: Calculation as the quotientcalculated the of administered AUC and dose therespectiveof concentration individual (C concentration half AUC and curve.The regression analysislinear theterminal of portion ofthe log concentration downand ofthe portions curve. elimination rate(λ The constant was estimat curvetime (AUC) ofzero thetime lastconcentration from quantifiable to (AUC Pharsight, 5.01; MountainView, the vs. plasmaCA). Area under concentration time parameters Pharmacokinetic were (Version software using estimated WinNonlin analyses:Pharmacokinetic
Acceptedcaffeine clearance, AUCand/orystemic plasma toparaxanthine caffeine metabolic Article - life ( life
(MRs) 5 t 0
1/2 in vivo in - t lasma and and urinary MRslasma were the indices calculated of as caffeine , where, C AUC (AUC ) was thequotient calculated as of0.693 andλ ed using thelinear ruleand logarithmicthe trapezoidal respectivefor up – 7 h7 caffeine after of administration
ma metrics of CYP1A2metrics of activity x ) and thetime C to ) and t
was the last measured concentration. The terminal terminal was last concentration. measured The elimination the 0 - ) from zero to) from infinity the was C as of sum calculated
max -
(t time curves. Total clearancecurves.time Total (CL/F) was max (26) ) were determined by visual inspection were by) visual determined inspection . In In . addition, urinary ratios metabolic are preferred (or and preferred are accepted)
z . The maximumThe plasma. 0 - . z
) was determined determined was by) . Therefore, the Therefore, vs . time t / λ z
0 - t ) This article isprotected rights by All copyright. reserved. correction. variance ( dosessinglemultiple and of efavirenz by werenonparametric analysis of evaluated between performed orenzymeparameters activity and of doses efavirenzmultiple single between was GraphPad Prism are expressed Data ±as Statistical SD. mean were analyses performed analyses: Statistical DMX =1,7 AFMUdimethyluric acid; = 5 Abbreviations: N XO ActivityCYP2A6 = ActivityCYP1A2 = Urinary MRs: activityCYP1A2 =P MRs: Plasma
AcceptedAT2 Article
Activity =
Activity = CYP2B6 Kruskall - using Correlation analyses dimethylxanthine (paraxanthine). dimethylxanthine dosing. dosing. Where (1 MU)/ (1 MX+1 (1 (1 MU)/ MU)
AF 1 MX = 1
the Software (
- genotype theactivities and CYP1A2 CYP2A6of and following Wallis test Wallis MU/ (AFMU+1 MU/ MU+1 MX). DMX DMU/1,7 1,7 DMU MUMX)/ +1 (AFMU+ 1 1,7 araxanthine concentrations ( araxanthine Caffeine Caffeine Wilco C
is plasma concentrationsis plasma at and 5 caffeine7 hours post - xon methylxanthine; 1 1 methylxanthine; MU = 1 La Jolla,CA,La USA) - ) acetylamino concentrations (
- using Dunn’spost matched paired test matched between efavirenz
- 6 - formylamino
C
. 5 hour + hour 5
Comparison pharmacokineticComparison of - C test comparison test for multiple 5 hour + hour 5 . exposure and enzyme activities and exposure For testing theassociation
-
methyluric 1,7DMU =1,7 acid; C - 3 7 hour) - methyluracil; and methyluracil;1,7and C 7 hour)7
using - This article isprotected rights by All copyright. reserved. to belonged other white/Caucasian + 22 and female; median of years28.5 age (range to 50 years); 18 weightbody 74.6 of the volunteers individuals efavirenzphases. treatment protocol Sixty Volunteers Human RESULTS involvesoften subjects. sample size15 than less to compared co as apriori calculation efavirenz’s on for effect dose 40%CYP1A2 detect powera in to difference singleactivity a efavirenz between size least sample ofsubjectsA at sufficient52 was as to provide calculated 95% a thanrather singledose when efavirenz administration Correlation (CYP1A2 CYP2A6) and were
Accepted kg; of and BMI 13.7 24.6 Article study
healthy normal volunteers were normal healthy recruitedand versus ofefavirenz doses multiple twoa at . However, . relativelyfrom a size data sample were study large analyzed this in The demographic The .
; this this ; Two participants
. after (rs) P lasma lasma was .
document Differences were judged to be to due chro
and ethnic/racial groups. nventional drug a pharmacokinetic pharmacokinetic wereparameters available n 19%were
exclusion s ofthe
ation of were one the excluded due to missingof samples from +
Caffeine were metabolic ratios calculated from 3.8 kg/m determined from the determined
black/African criteria 58
- exogenous exogenous drug interactions reporteddrug interactions in whichthe literature, CYP2A6, CYP2A6, XO and NAT2 participants 2
. .
Based on selfBased
- caffeine intake intake caffeine American. American. The
completing -
sided alpha level alpha of5%. sided Spearman's Rank c
ompleted theentire study - P identification,
< 0.05. nic efavirenznic treatment
the study were
was performed not by remaining
six from
individuals individuals 74
- only 52 Order Order
% ~7%
Power : 36 36 male : were 5
8
during This article isprotected rights by All copyright. reserved. 1 NAT2 to(range:45.4 281.4%) increased MRs subsequently. MRs c of doses after multiple efavirenz) (r efavirenz (r =0.33, ( singleefavirenzdose phase p by the individuals ( decreased 78.2 ( chronic ( Accordingly,c 0. The Table 1; Table Table P affeine affeine ). 01
Accepted Article <
% ) caffeine
0.0 as described in the in section. described as Methods (27) following
activities CYP2A6, XO CYP2A6, pharmacokinetics The c of 1 to to 31.7
efavirenz 001 lasma
MRs and . Thus, Thus, only . results from Figure CYP2A6 CYP2A6
(ranging from 28.9 )
, the , major of metabolite caffeine half Figure are are % hronic administration administration of hronic
MRs correlated withMRs correlated chronic % were not ) 1 -
(Figure 1 life
treatment the the preferred phenotype C ( P ). The ). The P activity
1
and ( < 0.0 A = and combination 0.013) of phasesboth (single dose and t 1/2
, efavirenz
(Figure P ) significantly NAT - was prolonged was prolonged 65.1 percent 001 B < 0.0
(
) decreased Table 1; Table .
Spearman rs - Similarly, ) 2 %
from
001 2 activities
compared compared to 43. affeine and metabolite are data shown in B)
plasma plasma change urine in s CYP1A2 CYP1A2 activity by measured ) .
5.7 = 0.57; P= 0.57; <0.0001) with marked Figure Urin altered altered by chronic efavirenz 2%) CYP1A2
CYP1A2 activity byCYP1A2 measured to
ary ( were
P MRs prese are
marker for marker for Chronic
3.6 = 0.57; <0.0001)P (Figure 1D)
to 2 < 0.
metabolic ratios metabolic A) .
a singledose ofa
after chronic treatmentafter with theRelative to estimated respectiveestimated caffeine from
decreased decreased 0001 with marked activity
interindividual variability
MR also variedMR also
efavirenz
) CYP1A2 CYP1A2 a .
nd AUC efavirenz (plasma MRs) (plasma CYP1A2 activity measured activityCYP1A2 measured [ nted nted as CYP1A2 markers of Figure the C
treatment inter
reflecting single dose
efavirenz rather and 0 S2 (A - max ∞
- exposure urinary MRs
subject variabilitysubject widely increased increased
after chronic of of than than -
u
paraxanthine
C)] by significantly XO and XOand rinary . among
. 38 phase
( urinary efavirenz Table 1 Table range: range: Plasma Plasma
(Table
percent ( P MRs in
< , the the - .
This article isprotected rights by All copyright. reserved. wasgenotype as groupedwith thegenotype *6/*6 CYP2B6*1/*6 CYP2B6*1/*1, dependent on wasdifferent, small in efavirenzDifference between *1/*1exposure *1/*6, and statistically although to compared genotypes doses multiple and of efavirenz (AUC exposure following studyanalyzed this published in and elsewhere in reduction greater CYP1A2). onactivity dependent efavirenz (the exposure CYP2A6 or CYP1A2 activity. activityCYP2A6 steady at singleor dose state AUC < 0.0 r correlation between: withobserved efavirenz shown higher as negatively by the significant exposure CYP1A2 of and CYP2A6 were efavirenz its metabolites, and in changes observed s
Accepted Article= - 0
01 0.32; P 0.32; <0. - 24h The correlation The analysis suggestthat Approximately 7 ). The percent change in CYP1A2). in percent waschange The negatively with efavirenz correlated
after multiple doses (r multiple doses after following a single dose and singledose following of doses efavirenz a multiple
CYP1A2 and CYP2A6 activit CYP2B6
( 01 Figure Figure : . ) as well efavirenz as AUC a singlea dose
To test whether thetest whether To of efavextent CYP1A2 - fold fold genotypes CYP2B6*1/*1 S 4) betweendifferences subject .
and ofefavirenzExposure correlate withdid not metabolites
correlations between efavirenz did did not activity Genotype s examined
= CYP2B6*6/*6 genotypes. of efavirenzof , analysesdata wasafter stratifying performed by - 0.41, P P 0.41, 0 significantly and efavirenzand AUC
- and 24 ies ) was) 2.5 - . phenotype the data subjects from same Greater reduction CYP1A2 in activitywas CYP2B6*1/*6 <
were
the extentof reduction CYP1A2 of 0.01 0 (AUC higher - 24h (30)
) dependent dependent - correla -
predicted phenotypepredicted was to close after multiple multiple doses (r after (Figure and 2 0
, (29) - ∞ the irenz ) was 2.1
-
te te in efavirenz 0 efavirenz exposure genotypes show that fold higherfold - ∞ S - with urine marker of with of marker urine One subject with *1/*18 CYP1A2 interaction is interaction CYP1A2 at singledose (Pear at 3).
on exposure and indices and exposure E
- the of exposure
. favirenz and 1.8 To test whether test To , efavirenz
in respectively exposure exposure CYP2B6*6/*6 - s
fold higher fold
exposure exposure = - 0.61, 0.61, P the was son . at ;
This article isprotected rights by All copyright. reserved. genotypes activityCYP2A6 was in lower genotypes, *1/*6 but notin theefavirenz urinary increased caffeine metabolic CYP2A6 ratio for *1/*1 and in of doses efavirenzmultiple (Figure 4B). among the ofwasCYP2A6 CYP2A6 induction also tested. activitystatisticallywas not different thewild from genotype type *1/*1 (A genotype 0.05 genotype (Figure 0.05, chronic phase, dose efavirenz activity CYP1A2 within< (P genotype each inhibited 3 *1/*6or *1/*1 ( slow metabolizer. Table Table A
Accepted Article- ) B) and )
, while, c (Figure 3D) The impact of impact of The S
multiple dosesmultiple of 1 s ) in bothin
, this , did statisticallylevelnota reach (Figure significant 4D). . when with compared *1/*1
CYP2B6 CYP1A2 CYP1A2
affeine AUCaffeine 3 genotypes C). . efavirenz treatment The The T Similarly, he
genotypes at either singledose of efavirenz orafter 4A) (Figure activity CYP2B6 demographic percent percent
following singledose
0 efavirenz ( - ∞
*6/*6 caffeine AUC caffeine and was genotype the CYP2B6*6/*6 lower for
*6/*6 genotypes ongenotypes theextentof efavirenz change CYP1A2 in
genotype (Figuregenotype change inAlthough percent 4C). CYP1A2 CYP1A2 in either
genotypes when s P
groups are and *1/*
< 0.01 Compared to thesingledosechronic Compared phase,
comparable thethree among 0
for *1/*6for were genotype the different not - treatment treatment ∞
was *6/*6 for higher significantly compared *1/*1 to genotype ;
6 ( Figure Kruskal
genotype
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compared with *1/*1 compared with and *1/*6 *1/*1 group 3 - B Wallis test, Wallis ) . s
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. (
Kruskal - P - mediated mediated Wallis test, Wallis
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[ Figure ; Figure P d d to
S <
5
This article isprotected rights by All copyright. reserved. Accepted(NN severalbiotransformation of nicotine the also metabolic pathwaynicotine main to the elimination and contributes for efavirenz that the it isanticipated would alter of drugs.these disposition is CYP2A6 metronidazole,clinically letrozole, drugs(e.g., tegafur)) efavirenz used and efavirenz treatment CAR and withtogether the that fact cytochromes P450 treatment NR1I3 involved in CYP1A2. Article clearance substrates.CYP2A6 Moreover, receiving efavirenz suggestdata dependent. Efavirenznotsignificantly did the altered increase efavirenzhigher those and exposure effect increased and DISCUSSION N),4
of of efavirenz ) Efavirenz activate thepresentIn study,
and pregnane (PXRand pregnane X receptor - in
(methylnitrosamino) (32)
enhances may drug CYP2A6 CYP2A6 activity
that
may explain the particularly
disposition,namely
there increased risk isan on on CYP1A2 in vivo
- . [ based HIV HIV therapybased who are e.g., e.g.,
CYP2A6 catalyzes the elimination s
CYP3A, CYP2B6CYP3A, and CYP2C19 activity of CYP2A6 isalso transcriptionally regulated t alter the risk for adverse risk the for alter wo nuclear receptors that regulate a range receptorsthat nuclear wo a ofgenes regulate our
chronic administration administration chronic of was neither was neither - 1
activity observed increase in CYP2A6 increasein observed activity - CYP2B6 (3 - pyridyl)
hepatic ofnumerous drugs the the - derived expressing
, was more was inpronounced individuals more fully or partiallyfully or NR1I2 constitutive (CAR receptor androstane
efavirenz genotypes - 1 CYP1A2 for for - butanone (NNK) butanone ( carcinogens ) drug
co (6) CYP2B6*6*6 - exposure , medicated withmedicated
-
drug interactions
(7) associated with efavirenz reduce drug interactions
and CYP2A6,respectively. The activit e favirenz reduce significantly . metabolized by the the metabolism of s of the metabolism Accordingly
(10) N y -
’
XO - nor nor (33) nitrosonornicotine nitrosonornicotine
, genotype (11)
or or C )
. Hepatic CYP2A6. Hepatic CYP1A2 or or CYP1A2 YP2B6 , N (12) , e ,
AT via
involving following in individuals individuals in favirenz ]
- while . , the . PXR 2 This This . genotype These (33) everal with (31)
,
and
d
- This article isprotected rights by All copyright. reserved. onadministered two (with ofefavirenz occasions multiple singledose after and the that is findings enzymatic inhibition efavirenz reduce to appear clopidogrel) and glucuronosyltransferases hydroxylated undergo metabolites hydroxyefavirenz, metabolites inactivatordependent) e CYP1A2 efavirenzactivityunknown. reduces remains efavirenz. of dose single a with administered was caffeine reduce (15) result also ofinteractions occur a as activationreceptor the n when co illnesses is volume,duration,topographyand velocity (puff withactivity been ofassociated number has favirenz isneither either efavirenz nor exposure
Accepted Articlecigarettethat conceivable smokers would atrisk increased be tobacco for magnitude , (34) In contrast to contrast the In d
. CYP1A2 activity activity CYP1A2 Our produce produce produce findings findings
of of (36) s the -
had effectno onhad prescribed efavirenz CYP1A2 CYP1A2 activity
clinically druginteractions. significant study design in which probe substrates including were which in caffeine studyprobe design occu a /inactivation ],
CYP1A2 increase in reversible nor inhibitor glucuronide glucuronide
clearly of of rs induction . of CYP1A2 activity
in vivo in With few exceptions With at relatively at
indicate that ch that indicate inhibition inhibition
the presence the the presence of
cannot
CYP2A6 compared to CYP1A2 activity determined when when determined activity CYP1A2 to compared effects of efavirenz conjugates extensive conjugation CYP1A2 CYP1A2 activity in vivo in direct direct enzymatic inhibition
low concentrations. efavirenz -
based HIV therapy. Our data therapy. Our HIV show that based be excluded. because
activity via (13) cigarettes smoked per smokedper cigarettes day,smoking a ronic doses of efavirenz significantly significantly efavirenz of doses ronic mechanisms other than other mechanisms are are mechanism
) and smoking cessation smoking ) and [e.g., glucuronides [e.g., ofgemfibrozil .
the It isunlikely suggest relatively CYP2B
in vitro in
major major
However, a limitation of these these of limitation a However, on gene expression, gene on In
The possibilityThe that vitro mainly ing - based ( 6 (13)
The mechanism mechanism by whichThe oxidative metabolite,oxidative 8 hydrophilic and hydrophilicdo and not
polymorphisms
that
studies that indicate that
. by efavirenz Efavirenz by
maximum maximum
i.e., i.e., efavirenz
direct direct time (33) drug -
-
nuclear nuclear . Thus, it altered altered related related (35) -
This article isprotected rights by All copyright. reserved. Acceptedg literature, of administration CYP2B6*18) and CYP2B6*6 and UGT2B7 CYP1A2, by variabilityinterindividual the likelihood abuse, tizanidine that and efavirenzco be may with individuals some infection HIV may also opioidsuffer from and be treated for symptoms associated with conditions.other Itand isfrequently presc (38) exposure upthe plasma to of tizanidine 30 inhibitors and increase ciprofloxacin For example, CYP1A2) (potent fluvoxamine of Article remolten tizanidine),and wouldlikely clinicall produce ranges narrow clozapine,possessing (e.g., olanzapine, duloxetine, therapeutic tizanidine) (e.g., pre significant exhibit interaction pre significant ofdrugpotential address induction bymetabolism efavi magnitude of CYP1A2 determine baseline did not true allowdetermination of the accurate of doses efavirenz)without inclusionof metabolism metabolism . Tizanidine isa. α Drug interactions withDrug to interactions efavirenz predict because of difficult the are note, theOf CYP1A2 caffeine, probe, lowhas reportedlikely here is underestimate an enotype efavirenz - systemic metabolism systemic via (37) single CYP2B6 - phenotype phenotype the data analyzed subjects thisfrom same in study . Thus, e Thus, . - 2 systemic (i.e., first (i.e., systemic - - adrenergic agonist approvedspasm agonist therapy adrenergic of muscle for CYP1A2 interaction CYP1A2 (30) (18)
in its plasma exposure its plasma in opiate withdrawalopiate , with minor contributionswith, minor , and (42) demonstrate favirenz co , multiple dosesmultiple (43) . The The . . P caffeine alone (absencearm efavirenz) of to atients - - pass) metabolism and low bioavailability bioavailability low and metabolism pass) administration with substrates CYP1A2 administration magnitude ofthe efavirenz magnitude ribed,off higher efavirenzexposure plasma - fold, concomitant toxicity increased fold, .. Initially, to study designed the was
during detoxification with (19) (41) - for any CYP1A2 drugs known to to known drugs CYP1A2 any for
label, suppressionfor of . variants in CYP2B6 geneCYP2B6 in (e.g., variants
of of efavirenz.
E from intrinsic clearance with no no with clearance intrinsic y significant drug y interactions. significant favirenz renz.
CYP2A6, CYP3A, -
administered is administered high.
is mainly
Consistent with the Consistent (39) - CYP1A2 CYP1A2 , (40)
eliminat . Becaus . marked marked the
after (37) ed
, e This article isprotected rights by All copyright. reserved. Thus,was a small. appearsand plausible sizeinteraction anticipated, sample our the CYP2B6*6/*6 for ofthe association ethnic compared populations other to and racial groups relevantfrequencies of genoty CYP2B6 this may particularly have consequences certain clinical in important population therisk efavirenzincrease for activityCYP1A2 in increase thatthat efavirenz suggest factors would exposure correlationanalysis withalong the showing efavirenz exposure the However, this also pregnancy the therapy efavirenz and exposure the co efavirenz may variantsgenetic in published and elsewhere
Accepted Article- CYP2B6*6/*6 infected with and infected HIV malaria,
decrease in lumefantrine in concentrationsdecrease CYP2B6*6/*6 contraceptive likely unique or American pose riskspopulationAfrican African in associated with differential dictates the dictates certain inductionmagnitude of druginteractions caused by has been . For example,
(44) is
particularly
in the in the first report suggestthereport to first genotypes to compared
subdermal implant genotype compared to genotype to *1/*1 compared genotypes. *1/*6 and These data associated withassociated lower levonorgestrelconcentrations CYP2B6*6/*6 well designed CYP2B6
in efavirenz lumefantrine reduced (30)
CYP2B6 in CYP2B6 CYP2B6 in - , CY (29)
gene gene contributesthat to efavirenz of metabolism autoinduction genotype on of efavirenzthe extent
P1A2 interaction. P1A2 (including alone arm) caffeine detailed and more resulting in
show efavirenz that exposure poor metabolizer
(22) poor pes (e.g.,*18) are and these in pes higher *6 CYP2B6*1/*1 genotype. , result greater reduction ofinCYP1A2 greater carriers of
metabolizers was
poor poor malaria treatmentresponse ing greater
The genotypeThe in a a in
s
(21) risk for (45) concentrations variableefavirenz exposure
in thosein .
CYP2B6 .
E . w Taken together, favirenz
- unintende dependentreduction is over 2 - with higher with higher Evidence exist that dependent effect
genotypes are - CYP1A2 CYP1A2 s - based HIV HIV based
in women withwomen in (20) as the as allele in patients d - fold fold . s
, e.g., e.g., , , and higher higher hile
This article isprotected rights by All copyright. reserved. expressi Accepted (NAT2). CYP2A6,enzymes: CYP1A2, xanthine N (XO)oxidase and work tested This Question Did ThWhat CYP3A) and drugmetabolizingselected CYP2C8, CYP2C9, CYP2B6, (e.g., CYP2C19, enzymes drugs. coadministered efavirenz While vivoin cause drug Efavirenz IsCurrent Knowledge the What on the Topic? STUDY HIGHLIGHTS Articleadverse efavirenz drug interactions. variants interactions non and genetic drugs efficacy of metabolized byenzymes. these activity validate our to and findings assess thetrue adequatestudy sample in size of - drug interactions In summary,In
and
on on the magnitude of interaction was on themagnitude ofinteraction on also tested. The impactThe of variationefavirenz genetic and in exposure and (e.g., Black African American) drug - - based HIV therapy HIV based based HIV therapy HIV is based . an
,
Finally,s its effect on other other its effect on enzymes effects
inducer inducer CYP2A6 of activity - genetic factors genetic factors the ofeffect
Concomitant use we demonstrated have .
, potentially compromising toxicity and efficacy of pecific population pecific
is Study Address? Studyis
will efavirenz associated complex often with and unpredictable will require CYP2B6
of CYP1A2 CYP2A6of and substrate increase on s expressing
careful such as such as
and the
genotyp that may be extent of efavirenz
the
in vivoin is
efavirenz inhibitor of CYP1A2 isan monitoring to monitoring to
risk for risk efavirenzfor mediated likely The results The further
CYP1A2 CYP2A6 and
e subgroups warrantede may be to at at
induction and/or inhibition of and/or of induction inhibition high hepatic activities of activitiesof hepatic four increased to to alter the alter er -
acetyltransferase 2 fre The The plasma and urinary minimize the - quencies of CYP1A2 interaction. CYP1A2 risk disposition and CYP2B6
suggest that suggestthat for efavirenzfor
drugs
is CYP2B6 risk of unknown. - drug with
This article isprotected rights by All copyright. reserved. the data. Y I Author Contributions: inparticipated thestudy. coordinatingUniversity), study theclinical who for the healthy and volunteers Acknowledgements: adverse riskfor increased involvingparticularly drug interactions at CYP1A2. Moreover, willtherapy use CYP2A6 ofand Concomitant CYP1A2 substrate drugswith efavirenz Change MightPharma This Clinical How genotype is CYP2B6 substrates. Th suggesting efavirenztheenhances elimination likely ofCYP2A6 chronic exposure isthe firstThis clinical efavirenzstudy showing hepatic and CYP1A2 that reduces This Does StudyWhat Add Knowledge? ToOur chronic as (N =58) single of a dose caffeinedisposition mg oral 150 of in was healthy profiled volunteers . F . K
Accepted. Article M . , . and , N
efavirenz 17 days.for treatment .
D J CYP2B6 genotypes associated with genotypes CYP2B6 increased efavirenz may exposure be . . , R B in vivoin require careful careful monitoring to riskofrequire minimizeadverse the drug effects. . L is also report first the to the extent of efavirenz . E . L . . G
performed I theresearch; probes following dose mg oral single600 of efavirenz a after and .,
and Z - dependent. We wouldlike to thankRN,We NP Nancy Thong, (Indiana
. D .
wrote the Z article;
cology Science Translational or . F . M . , N . D .
.
D designed the I research; . , R . E . G ., - CYP1A2 interaction CYP1A2 and Z . D .
- analyzed based HIV HIV based . F ?
. M
. , This article isprotected rights by All copyright. reserved. References (3) (2) (1) Accepted(6) (5) (4) Article
CAR Inducer EfavirenzCAR Inducer Vivo. In HK, Kroemer Z, Desta zuMeyer HE Schwabedissen Bristol Bristol treatingdrugs for and infection,preventing2nd HIV edition. HealthOrganization.Consolidate guidelinesWorld on theuse of antiretroviral Accessed http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf ofDepartment Health Human Services.and Avail Use in of Antiretroviralthe with Agents Adults and Adolescents HIV. Adultson Panel Antiretroviral Guidelines and Adolescents.for Guidelines for 120 Pediatricadolescents: Clinical AIDS Trials efavirenz and didanosine, HIV in Long C, Hu Rodman J, Britto Jr.,MEal. McKinneyP, Smith RE, M, Hughes et initial treatment the of HIV et al. III Triple HJ, RM,Ribaudo Gulick Shikuma CM,Lustgarten Squires KE,MeyerS, WA, , e416 -
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This article isprotected rights by All copyright. reserved. (13) (13) (12) (11) (10)
Accepted Article(9) (8) (7)
2B6, 2C8, 2B6, 2C9 and 2C19. (CYP)of P450 cytochromeinhibition eight enzymes:major effects on CYPs Z.vitroquantitative efavirenzXuIn Desta analysis C,and of prediction efavirenz patients. HIV in and Pharmacogenetic aspects CYP3Ainductionpharmacokinetic of by Habtewo 475 of administration efavirenz healthy in volunteers. Z. Michaud V Ther on pharmacokineticsmethadone and pharmacodynamics. K,Crafford Stubbert A, A, London Kim T. ED, D, Kharasch HofferEnsign D, PS,Campbell C,Bedynek S, Whittington Pharmacol Ther efavirenz its and HIVoneffect plasma in exposure patients. autoinduction MugusiNgaimisi S, E, MinziRiedel KD, P, A Suda Sasi et Long OM, al. Discov Kliewer Willson TM, SA (2013) reverseinhibitors.transcriptase nucleoside byreceptor etravirine: with rilpivirinegenerationcomparison and non first D, Sharma Lau AJ, ChangSherman MA, human Agonism of pregnane XTK.
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91 .
(2012) 1 ld A, Amogne W, A, Makonnen ld Amogne Yimer W, KDE, al. Nylen G, Riedel et H, , , 673 , Ogburn, Aregbe E, N, Thong AO,DA, Flockhart Quigg TC, 259 - .
84 - 66 .
88 (2012).
(2002) ,
67 . PXR,. anddrug CAR metabolism. 6 . -
Pharmacogenomics J
84 Drug Pharmacokinet Metab
(2010) .
Mechanism ofefavirenz influence Biochem Pharmacol
. ClinPharmacol Ther 1 3 , 484 .
28 - 9 NatRev Drug , Clin Pharmacol
(2013) 362 - ; 71 85 .
(2013) , :1700 . Desta - 91 term term - - . , Clin 11
This article isprotected rights by All copyright. reserved. Accepted (19) (18) (17) Article (16) (15) (14)
Ther CYP2B6 Implementation ConsortiumClinical Pharmacogenetics (CPIC) Guideline for Z, RS, Gammal Desta L, Gong Whirl Ther Exp CYP2B6efavirenz substrate of cata marker a as HIV/AIDS Implicationsecondary therapy metabolism: for utility and of (CYP2B6)cytochrome P4502B6 catalyst isthe main efavirenz of and primary JonesBA, DR,HallWard Gorski JC, Desta FlockhartZ. DA, SD, The Chemother the pharmacokinetics isoniazid of acetyland of Effect efavirenz McIlleron ChirehwaAffolabi H, MT, L, D,Bah Wiesner healthyin volunteers. inductionStereoselective and inhibition bupropion of metabolism by efavirenz Masters AR,JB, BT, DR,DestaMetzger Z.Gufford Lu Jones IF, healthy in volunteers. amodiaquine ofefavirenzadministration concurrent kinetics of disposition the on Onyeji Soyinka JO, Nathaniel Odunfa OO, BU. CO, TI, Ebeshi (2013) children vary in concentrations genotype. by CYP2B6 rifampin of Effects HM,Schomaker Y McIlleron M,Ren .
. Apr 21.doi: 10.1002/cpt.1477
. and Efavirenz
306 .
; 74 , 287 , - 139 - bas based antituberculosis antituberculosis based plasma therapyefavirenz on - 300 (2003) - ClinPharmacol Ther ed antiretroviraled high therapy and 48 - containing Antiretro containing
(2019)
.
J Pharmacy Res , Sinxadi , Nuttall GousHetal. P, JJ,
- (2019) Carrillo M, Gaur AH,CarrilloM,Gaur Sukasemal. Cet . . [Epub. ahead ofprint]. viral Therapy.
- 101 isoniazid.
lytic activity. ( Suppl Suppl 1 . - AIDS Sow O, Merle C et SowMerle Cet al. O, 6 J Antimicrob - , 275, dose rifampicin on dose rifampicin on ) Clin Pharmacol ClinPharmacol , S66, .
- J Pharmacol and 27 279 Effects of of Effects
, ( 2017 1933
(
2013 ) - . 40
) .
This article isprotected rights by All copyright. reserved. Accepted (25) (24) (23) Article (22) (21) (20)
Driving Caffeine Consumption.Driving Caffeine Interindividual CaffeineNehlig Differences in A. Metabolism Factors and 2012 NAT2 CYP2A6, and XO. variation factors in disp for caffeine Djordjevic. Natasa of pharmacogenomic and Importance environmental J Exp in metabolites man. Pharmacol Ther Tang ClinPharmacol Ther Combined Antiretroviral Containing EfavirenzWith Nevirapine. Therapy or of Effectal. Gene The Variants on LevonorgestrelPharmacokinetics When M, A,Neary KM, Olagunju Darin Merry M,Lamorde Byakika C, 95 HIV in response withassociated low and plasma exposure poor treatment lumefantrine high and concentrationgenotype efavirenz but not nevirapine plasma are BA,Minzi Maganda KamuhabwaNgaimisi OM,Aklillu E, E.CYP2B6*6 AA, Ther exposurewith HIV plasma in withouttuberculosis. patients or rifampicin and CYP2B6 long genotype on MugusiNgaimisi S, Suda Riedel KD, et E, MinziA P, al. of Effect Sasi O,
(2016) . ). -
Liu DD,Disposition Liu caffeine its RiegelmanS. and RL, of Williams 90
,
406 - 13 - malaria
( 2011 . 102 ). -
coinfected coinfected patients.
Thesis/Dissertation , 529 Pharmacol Rev - 36
osition: with special emphasis onwith special emphasis osition: CYP1A2, (2017 ). - term efavirenz term and autoinduction
.
224
Ph , 1 . - armacogenomics J , 48 (Karolinska 48 Institute, 70 180 , 384 - 5
(1983). (1983). - 4 11
(2018) ClinPharmacol - Kibwika P etP Kibwika
. .
1 6 , 88 - This article isprotected rights by All copyright. reserved. Accepted(3 (31) (30) (29) Article (28) (27) (26) 2) 2)
Identification of a novel ofa (CAR)Identification human constitutivereceptor androstane Maglich DJ, CollinsParks JL, LB, JM, Moore B, Goodwin etBillinal. AN Exp Pharmacol Ther peroxisome proliferator Induction of human CYP2A6 ismediated pregnaneby X with the receptor M, M,HigashiItoh Nakajima YoshidaNagata R, E, K, Y Yamazoe etal. Chemother non and Population pharmacokinetic thecontribution modeling to estimate of genetic Robarge Electrophysiol Interval QT Induces Prolongation CYP2B6*6*6 in Allele Carriers. Efavirenzthe Ether Human Inhibits ShuggAbdelhady AM, N,JB,KreutzThong Lu T, al. Y, et Jaynes HA geno Efavirenz Kreutz Michaud V, Y, E,Skaar Ogburn T, Flockhartet N, DA Thong al. Curr Drug Metab N Hakooz ratios NM.Caffeine metabolic vivothe CYP1A2, in for of evaluation 109 paraxanthine/caffeine ratio in plasma saliva.and in U,Rost and reliableKL. Simple Fuhr CYP1A2 phenotyping by the - acetyltransferase oxidaseacetyltransferase 2, xanthine and enzymaticCYP2A6 activities. - 16 type dependent.
(1994).
genetic genetic efavirenz factors of disposition. JD, MetzgerJ, Lu IF,Skaar TC, N, Thong - mediated induction induction of omeprazole isCYP2C19 metabolism mediated .
61 .
, 1 27 . - , 1206 10 17 . ,
Pharmacogenomics J
( 329 319 2016 - activated receptor activated - 13 (2016).13 , - 38 693 ) .
(2009). (2009). - 702 - A
(2006). (2006). -
Go - Go Related Current (hERG) Go Current Related and - gamma coactivatorgamma 1alpha.J .
14 , Antimicrob Agents 151 Pharmacogenetics Desta Z - 9
(2014). (2014). ,RR Bies
J Cardiovasc J Cardiovasc . .
4 , This article isprotected rights by All copyright. reserved. Accepted (38) (37) (36) Article (35) (34) (33)
potentially hazardous interaction.potentially hazardous Fluvoxamine drastically and concentrations ofeffects tizanidine: increases a MT,Backman Granfors Neuvonen M, JT, Neuvonen Ahonen J, PJ. Ther 1A2cytochrome P450 concentrations hypotensive and increases of tizanidine effect by its inhibiting MT,Backman Granfors Neuvonen M,NeuvonenPJ. JT, Ciprofloxacin greatly ClinP CYP2C8: phase of a II as perpetratorofmetabolite a drug converts strong Glucuronidation al. a time to clopidogrel Filppula A, Tornio AM, Neuvonen M, Kailari O, Nyronen et T TH, Tapaninen Dispos ofCYP2C8: implications inhibitor drug for convertsGlucuronidation a gemfibrozilpotent, metabolism to Zhang RodriguesOgilvie AE,Holsapple D, Gipson BW, AD, Li Jal. et W, Antimicrob Chemother Agents have men lowor are international implications weight: for guidelines. dosing antituberculosisReduced drug concentrations HIV in VahediRustomjeeDenti R, H,M,Mthiyane P,McIlleron Connolly T, al. Cet Medicine. Ta 278 itsin and agonist use theidentification CAR of genes. target nner JA,RF. nner CYP2A6 in Tyndale Variation Activity Personalized and , . 17277
harmacol Ther 76 .
34 , 598 J Med Pers , - 83 191 -
606 (2003). - 7
(2006). (2006). (2004). . .
- 96
mediated presystemicmediated metabolism.
7 , ,
1 498
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56 2017 ClinPharmacol Ther ,
(2014). 3232 ) .
- - 8 drug interactions. drug interactions.
(2012).
- infected patientswho .
- 75 dependent inhibitor - ClinPh drug interactions. drug interactions. , 331 Drug Drug Metab J Biol Chem - dependent - 41 armacol
(2004). (2004). .
This article isprotected rights by All copyright. reserved. Accepted (44) (43) (42) Article (41) (40) (39)
Contraceptive Implant and ContraceptiveEfavirenz Implant and CombinedObserved Pregnancies Unintended Use of the Levonorgestrel With Darin Scarsi KK, S, KM, BackNakalema DJ, Byakika efavirenzof 7 metabolic pathwaysP450 cytochrome (CYP)as the principal catalyst and 2A6 secondaryand in metabolism vitro in vivo: and identification ofnovel JonesXu AR, C, ET, Z.Ogburn DR,Masters Guo Y,Desta Efavirenz primary Dispos Metab vitro in investigationan drug of oftheC. Glucuronidation antiretroviral drug efavirenzand by (EFV) UGT2B7 AS,Ca Belanger (2007). HIV in concentrations knownPredictive valueof alleles novel ofCYP2B6 efavirenz and for plasma H,S,Rotger M,CavassiniTegude Colombo Furrer H,Decosterd M, et al. L CD002024. doi: 10.1002/14651858 ( management of opioid withdrawal. Gowing (2008). healthy patients.effectiveness in and subjects relationships dose tohydrochloride pharmacokinetics, drug safety and review clinically tizanidineA HR,III,JD. Henney Runyan relevant of
L, Farrell M, Ali R, White JM. Alpha(2) JM. Farrell R, M,Ali L, White - . hydroxylation. hydroxylation.
37 ron P, Harvey Guillemette PA, Mehlotra RK, M,Zimmerman , 1793 - infected individuals. - 6 (2009). (2009). 6 Drug Me Drug - drug interaction (AZT). with zidovudine Cochrane SystCochrane Rev Database
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This article isprotected rights by All copyright. reserved. and after dose of doses efavirenz multiple doses(multiple versussingledose ofefavia and described (N=58). (A), doses after multiple of efavir Relative 2. Figure doseopen CYP2A6 (SD, single circles) following and activity test rank and after dose of doses efavirenz multiple versusa doses single of dose efavirenz) are activityCYP1A2 MRsplasma in using surrogate the relativefor CYP1A2change in in activity. percent changes Ranked (N=58). doses after multiple of circles) inhealthy efavirenz (MD, closed volunteers Relative 1. Figure doseopen CYP1A2 (SD, single circles) following and activity legends Figure Accepted Article (45)
70 implications UGT2B7: HIV/AIDS treatment.for Worldwide variation in drug human Menard J,V,Li BenishJurevic RL, RJ,GuillemetteC, Stoneking M al. et (2016). Pharmacokinetic Arm OveEvaluation
Plasma Plasma . ****P. <0.0001.
(2012). (2012). CYP2A6 activity was activityCYP2A6 calculated from urinary metabolicratios as caffeine
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and urine and urine metabolism enzymemetabolism CYP2B6 genes and was compared using using compared was using compared was r 48 Weeks. renz). CYP2A6 activity CYP2A6 renz). following single shown. CYP1A2 activityshown.CYP1A2 following single
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This article isprotected rights by All copyright. reserved. Accepted compariso Dunn’s hoc multiple wasgenotypes ANOVA tested (Kruskal using nonparametric genotypeefavirenz each in using versus genotype group.each efavirenz. singledose ofefavirenz.a volunteersefavirenz inhealth (MD) (N=58). *1/*6, Relative 4. Figure CYP2A6 by activity stratified statisticall NS, P<0.05. not post was usingamong genotypes ANOVA tested (Kruskal nonparametric Article efaviof CYP1A2 in change activity. SD activity betweenwas a and MDs CYP1A2 compared efavirenzmultiple genotype within group. dosing each chronic ofefavirenz.activity administration after activity. paraxanthinemetabolic ratio to Plasma of caffeine representsrelative CYP1A2 dose and single multiple volunteers dosesofefavirenzhealth in (N=5 Relative 3. Figure CYP1A2 activity stratified efavirenz). test rank - hoc Dunn’smultiplecomparison****P<0.0001, test. ***P<0.001,* **P<0.01, n=15; and n=15; and
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- This article isprotected rights by All copyright. reserved. Accepted Article Tables Supplemental Figures and Tables Figures) (Supplemental and SupplementaryMaterials
AUC C T TMX) (1,3,7 Caffeine NAT XO CYP2A6 CYP1A2 Urinary MR MR Plasma in Change EnzymeRelative Activity T AUC C T (1,7 MX)Paraxanthine T This article isprotected rights by All copyright. reserved. concentration the plasma under T of doses efavirenz)multiple * acetyltransferase 2 (minimum are expressed Data ±as SD mean dose and single after dosesofefavirenz. multiple urinary ratios(MRs) metabolic paraxanthine 1.Pharmacokinetic Table parameters ofcaffeine max max 1/2 1/2 max max P max ‡ Accepted Article (hr) (hr) < 0.05,
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N - This article isprotected rights by All copyright. reserved. Accepted Article
This article isprotected rights by All copyright. reserved. Accepted Article
This article isprotected rights by All copyright. reserved. Accepted Article
This article isprotected rights by All copyright. reserved. Accepted Article