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22-244 Biopharmaceutics Review(S) CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-244 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) DEP\RT\IE.'\T OF IIEALTH .\ '\ D Clinical Pharmacology & Biopharmaceutics IH\L\!\ SER\ICES PI HUC IIE\LTH SERVICE (HFD 870) FOOD\'\D DRIG .-\D\""ISTR\TION Tracl"ingl Action Sheet foi' Foi'malllnformai Consults . Iniiii: \rikdllih C. '\dll.lIi_ I'h.I), To: DOCl'\'IENT ROOi\l (LOG-IN and LOC-OlT) Please log-in this consult and review action for the specified IND/NDA submission 1); I I.: II I X::I)I)X ~;\~) :\u.: ND.\ :\u. :::: - ::-1-1 I),\TI 01 DOel "II.NT IIJ' 1:1/::()IJX Sni.11 :\u.: IV-IJIJIJ Class I Resuhiiission '\.\\11.01 imi(, l'I~IORln (()'\ \11)1 R\II ()'\ J).lIC ui' illl,)lli.il.;lmlldl I IJ I Y::()IJX I LlCEDR.\ (Fospropofol) Standanl (ulisLlli: Injection I 1111 :\/\\11 01 \I'O'\\OR: I \1(;1 Pharma I TYPE OF SL InIiSSIO,\ CLI'\I( .\L PIIARMACOI,O(;YIBIOPIL\R\L\CEITlCS RELATED ISSUE o I'I~I.-I:\I) 0 1)IS\OI.11 IO:\I:\-\III~O 1~1I.1 ..\SI. 0 IIN/\1. I'RI1\III) 1..\131 1.1:\( , 0\:\1\ 1\111' III \1\:\ \(\1 IN(i o 1311h \1\11./\131111 Y \ 1(1)11\ ~ L\l31I1NCi RI. VISIO'\ i:\-\iiim \111 ,\HI)I 0 1\\1 0 I "i - \ I \ 0 \\\ I \ I J( i~ Ii)l lSi o (ORRI\I)ONI)IMî o I'R()lI)(.I)1 o Si '1)\( I~II\TII) 0 IWI.(j /\I)VIRTI\I:\( j 01'11\\1. 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'\1 E'\T(S) 0'1.:11) TO in (O\I\I! '1(\11:1) TO TilL ~I'O'\\OR ~ 11\\1: in:i'\ CO\!\! 1'\ 1(\11:1) TO TI! L ~PO'~OR (()\ i '\ I E.'\TV" PEeL\ L I '\STRI (TI O!\S: I I Ii I.J)R\ (li'sl'n'I'I'li\1 elisudiLlIl iinil'i'iiiiii is .111 iiiii..ii cil"L1s Si'd.iiii i'-h:, Jìiiuiic :i!:i'1l1 ilidii~.llL'd I"r si'd.iiiiiii iii .idlill p.llii'lits L1lldCT!:1 iiii!: eli.I!:1l1 'sl ii. ,'r IlilT.i¡'i'lIl ii. I'n'i.celiiri's. \I( ,i I'h.iriii.i's "ri!:ili~11 :\1)\ d.ikd 1)::h::IJIJi 1I.IS iiul :lPl'niii'd (i::::::I)()i) ellil' I" I.ii'k l,r:idl'LJlI.ilc ilili,rli:iii,,1l II' SlIJìI'''rlllii'l'nil'''5:lllh.11 i'nii iders i':l1l s:ll.l'l:' Illdn.i!:i' si'd.iiiiiil "r 1'~llii'lltS II iih l,islmiJì"rl'l. In l.l'SI'''11Sl'. \)11 II) I.~ ::I)IIX \Ii ii .siihliiiill'eI.i (î:iss I l.l'SlIhliissi"ll II iih.i rn iSi'd Jìr"JìI'5:i1I1' lISl' I.I( ÎI)I~,\ J,ir Ili)niiiircd .IlCSthi'si.1 i..iri' i,ir Sl'il.iiiiiii in .ldLlIII,.liii'llis lIlidlT!:uili!: di.I!:llIsiIC ul.lhn.ll'l'llic imil'i'diircs. I his siihilissiiiii ducs IlUli'I)IlI.lin .111:'Ill'ii cl i il ii..i1 Jìh.irlii:ii'I'11 i!:1 ililillïlLllil'll. l'Ie"IS,' Sl'l' thi' "ri!:in.11 :\1).\ cliliii'.11Jìh.irii.ii.i )1, i!::, rn ii'lI d~lli'd h::.ì::IJIIX I,ir ihi' 1.lhi'lili!: I.l'l', \ il il l'il eI.11 i"IlS PlTI i Ili'iii 11' c.liii ii',11 ph.lliii.li'ul, )!::' elisl'il'l i ni'. I SIG'\\Tl in: OF RE\ I E\\ E I~: Sril,allth Co '\allaiii Ph.D, I ).lll' I i -I X-::IJIJX \ I (; '\.\ Tl in: OF TE.\.\I I.L\DER: Siin'sh J)oddaiiallt'iii. Ph,D, I ):lli' I 1- i X-::IJI)X (Co: II FD # I I: II.: I I Project IVlaliagei': Date This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. / s/ Srikanth Nallani i i / i 8 / 2008 0 i : i 3 : 54 PM BIOPHARMACEUTI CS Suresh Doddapaneni i i / i 8 / 2 0 0 8 0 i : 4 0 : 24 PM BIOPHARMACEUTI CS CLINCAL, . - . .. PHACOLOGY REVIEW NDA: 22-244 Submission Date(s): 09/26/2007 \\\1,) Proposed Brand Name To be decided betwoen "LuHèra" Generic Name Fospropofol disodium irYection Clinical Pharmacology Reviewer Srikanth C. Nallani, Ph.D. Pharmacometrics Reviewer Venkatesh Atul Bhattaram, Ph.D. Pharmacometrics Team Leader Joga Gobburu, Ph.D. Team Leader Suresh Doddapaneni, Ph.D. OCP Division Division of Clinical Pharmacology II OND Division Anesthesia, Analgesia and Rheumatology Products Sponsor Eisai Pharmaceuticals Inc. Relevant IND(s) 62,860 Submission Type; Code New Molecular Entity, 1 S Formulation; Strength(s) Injection; 35 mg/mL Indication Procedural sedation Proposed Dosage Regimen In adults aged 18 to ..65 years who are healthy or have mild systemic disease (ASA PI or P2), the standard dosing regimen ofFospropofol is an initial IV bolus of 6.5 mg/kg followed by supplemental dosages of 1.6 mg/kg IV (25 % of initial dosage). Adults ::65 years of age or those with severe systemic disease (ASA P3 or P4) should receive initial and supplemental intravenous dosages of75 % of the standard dosing regimen. Table of Contents 1 Executive Summary ..................................................................................................... 3 1.1 Recommendation ... ..... ...... ........... ....... .... ............... .... ......... ....... .... ........ ........... ..... 3 1.2 Phase IV Commitments ..... ...... .... ....... ........ .................... ...... .... ............... ........ ...... 3 1.3 Summary of Clinical Pharmacology Findings....................................................... 3 2 QBR............................................................................................................................13 2.1 General Attibutes................................................................................................ 13 2.2 General Clinical Pharmacology...........................................................................13 2.3 Intrinsic Factors ................................................................................................... 32 2.4 Extrinsic Factors..................................................................................................37 2.5 General Biopharmaceutics...................................................................................42 2.6 AnalyticaL............................................................................................................. 43 3 Labeling...................................................................................................................... 48 4 Appendix ..... ........ ....... .... .... ....... ...... .... ......... ...... ........... ........ ............... ......... ........ ..... 55 1 4.1 Proposed labeling ................................................................................................. 55 4.2 Pharmacometrics Review by Dr. Atul V. Bhattaram .......................................... 67 4.3 Individual Study Synopses: ...........................,................................................... 111 4.3.1 Mass Balance Study # 3000-0205 synopsis................................................ 111 4.3.2 In vitro protein binding offospropofol and propofol................................ 117 4.3.3 Influence of Time and Temperature on Metabolism ofFospropofol (GPI 15715) by alkaline phosphatase ............................................................................... 126 4.3.4 Metabolic stability offospropofol (GPI 15715) in liver microsomes......... 130 4.3.5 Study # 3000-0001 Synopsis ...................................................................... 132 4.3.6 Study # 3000-0102 Synopsis ...................................................................... 137 4.3.7 Study 3000-0103 Synopsis ......................................................................... 141 4.3.8 Study 3000-0206 Synopsis ......................................................................... 149 4.3.9 Study"3000-0308 Synopsis ......................................................................... 155 4.3.10 Study 3000-0414 Synopsis ......................................................................... 158 4.3.1 1 Study 3000-0401 Synopsis ......................................................................... 165 4.3.12 Study 3000-0402 Synopsis ......................................................................... 169 4.3.13 Study 3000-0521 Synopsis ......................................................................... 173 4.3.14 Study 3000-0625 Synopsis ......................................................................... 180 4.3.15 Study 3000-0207 Synopsis ......................................................................... 186 4.3.16 Study 3000-0415 Synopsis ......................................................................... 189 4.3.17 Study 3000-0520 Synopsis ......................................................................... 195 4.3.18 Study 3000-0522 Synopsis .........................................................................204 4.3.19 Study 3000-0523 Synopsis .........................................................................211 4.3.20 Study 3000-0524 Synopsis .........................................................................216 4.3.21 Filing Memo...............................................,................................................224 2 1 Executive Summary 1.1 Recommendation The submission is acceptable
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