`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`21-660
`
`APPLICATION NUMBER:
`
`PHARMACOLOGY REVIEW! S!
`
`
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`21, 660
`
`000
`
`DATE RECEIVED BY CENTER:
`
`03/07104
`
`PRODUCT:
`
`ARI—007
`
`INTENDED CLINICAL POPULATION:
`
`-—
`
`SPONSOR:
`
`American Bioscience, Inc.
`
`DOCUMENTS REVIEWED:
`
`Electronic submission
`
`REVIEW DIVISION:
`
`Division of Oncology Drug Products (HEB-150)
`
`PHARM/TOX REVIEWER:
`
`Margaret E. Brower, PILD.
`
`PHARNI/TOX SUPERVISOR:
`
`John Leighton, Ph. D.
`
`DIVISION DIRECTOR:
`
`Richard Pazdur, M.D.
`
`PROJECT MANAGER:
`
`Sheila Ryan
`
`Date of original NDA review submission to Division File System (DFS): 12/ 17/04
`
`
`
`
`

`

`Reviewer: Margaret E. Brower, PhD.
`
`NDA No. 21,660
`
`TABLE OF CONTENTS
`
`Page
`
`1.
`
`ll.
`
`EXECUTIVE SUMMARY ................................................................................ 3
`
`SUMMARY OF NONCLINICAL FINDINGS .................................................... 3
`
`2.6
`
`PHARMACOLOGY/TOXICOLOGY REVIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY ................... . ................................... 5
`
`2.6.2 PHARMACOLOGY ........................................................................................... 9
`
`2.6.2.1 Summary
`2.6.2.2 Primary pharmacodynamics
`2.6.2.3 Secondary pharmacodynamics
`2.6.2.4 Safety pharmacology
`2.6.2.5 Pharmacodynamic drug interactions
`
`2.6.3
`
`PHARMACOLOGY TABULATED SUMMARY ............................................ 10
`
`2.6.4 PHARMACOKINETICS[TOXICOKINETICS ................................................. 10
`
`2.6.5
`
`PHARMACOKINETICS TABULATED SUMMARY ..................................... 17
`
`2.6.6
`
`TOXICOLOGY ............................................................................................... 18
`
`2.6.6.1 Overall toxicology summary ............................................................................ 18
`2.6.6.2 Single-dose toxicity ........................................................................................ 19
`2.6.6.3 Repeat-dose toxicity ........................................................................................ 23
`2.6.6.4 Genetic toxicology .......................................................................................... 24
`2.6.6.5 Carcinogenicity ............................................................................................... 24
`2.6.6.6 Reproductive and developmental toxicology ................................................... 24
`2.6.6.7 Local tolerance ............................................................................................... 30
`2.6.6.8 Special toxicoiogy studies ............................................................................... 30
`2.6.6.9 Discussion and Conclusions ...............................-............................................. 3 2
`
`2.6.6.10Tables and Figures .......................................................................................... 32
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY ................................................... 32
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS .......................... 33
`
`APPENDIX]ATTACHMENTS ........................................................................ 34
`
`

`

`
`
`Reviewer: Margaret E. Brewer, PhD.
`
`NDA No. 2i,660
`
`I.
`
`Recommendations
`
`Executive Summary
`
`A. Recommendation on Approvability: Approve
`
`B. Recommendation for Nonclinical Studies: Approve
`
`C. Recommendations on Labeling: See separate labeling review
`
`II.
`
`Summary of Nonclinical Findings
`
`A. Brief Overview of Nonclinical Findings
`Abraxane is composed of a Cremophor-free formulation of paclitaxel formulated in human serum albumin. The
`name Abraxane refers to the clinical formulation of the drug product used in Phase 3 studies, which is to be used
`commercially. This name refers to the natural biosource material, T. media, and a ratio of 1:9: paclitaxel: human
`serum albumin. Other biosource materials (manufactured by differing suppliers) of the drug used for pre-clinical and
`earlier clinical trials included
`.
`""""
`.paclitaxel. Suppliers of
`human serum albumin and ratios of paclitaxel to human serum albumin have also varied during the development of
`this Taxol analog. Names for the drug used for pro—clinical studies with these varying biosource and human serum
`albumin concentrations are known as Capxol and ABl-OOT. Pre—clinical pharmacokinetic studies comparing the
`differing biosource formulations and differing paclitaxel to HSA ratios have indicated only minor changes which
`would not significantly impact the comparative toxicity of the drug. However, since the natural biosource was
`utilized for Phase 3 studies and will be used commercially. it should be noted that this ABl-007 biosource exhibited
`a slightly higher systemic exposure, with an extended half-life compared to the
`.—-—-
`---r
`biosources.
`
`In general, acute toxicity and lethality of ABl-007 were significantly reduced as compared to Taxol, based on
`comparative lethal doses and MTDs. However, renal toxicity was observed in multiple toxicology studies with ABI—
`DOT-dosed rodents. Single—dose studies with ABI-007 in rats indicated renal toxicity at doses >540mg/m2. in these
`studies, lethality was observed at doses >720ntg/1112 and myelosupprcssion was reduced compared to Taxol. Rats
`administered ABl-007 exhibited swollen nerve root axons of the spinal cord at 540mg/m2, and urinary bladder
`hyperplasia, kidney fibresis, adrenal hyperplasia, and testicular atrophy at doses 354mg/m2; these findings were not
`observed with concurrently administered Taxol animals. in rodent pharmacokinetics studies, ABI-007 appears to be
`rapidly distributed to tissues with a greater volume of distribution and longer serum half-life compared to Taxol.
`
`Toxicology studies in dogs, and possibly swine were complicated by the immunological reaction of the human
`albumin to these animal models. Even so, neurotoxicity of ABl-007 in dogs appeared to be enhanced compared to
`that of Taxol.
`
`Abraxane is embryotoxic and fetotoxic when administered to rats at doses 36mg/m2, (approximately 0.02 of the
`daily maximum recommended human dose on a mg/m2 basis) on gestation days 7-17. Significant changes in
`reproductive parameters included increase of early and late resorptions ( 4.5 fold), reduction in litter size and live
`fetuses ( up to 3-fold), significant reduction in fetal BW and significant increase in numbers of fetuses with
`abnormalities. All fetuses were born dead or resorbed at 24mgfmZ in this study. Biologically significant fetal
`anomalies included fused digits, bulging eyes, folded retinas, microphthalmia, dilation of brain ventricles, septal
`defects in heart vasculaturc, fused lungs, small eye sockets, presence of extra cervical ribs, and incomplete or absent
`ossification of ribs and sternum. Eye anomalies and extra cervical ribs were also observed at the lowest dose tested,
`3mg/m2. In another study, significant changes in reproductive parameters included significantly reduced sperm
`count and sperm motility, absence of implantations and viable embryos, absence of fertility index, significant
`reduction of dams with viable fetuses, and maternal lethality. Testicrrlar atrophy/degeneration has also been
`observed in single—dose toxicology studies in rodents administered Abraxane at 354mg/rn2 and dogs administered
`l75n1g/n12.
`
`B. Pharmacologic Activity
`The effects of Taxol and ABI—OO'i on tumor free survival and tumor growth rate were compared for HT29 colon
`tumor, PC-3 prostate tumor, NCI-H522 lung tumor. SK-OV-3 ovarian tumor and MX-l mammary tumor. Abraxane
`
`3
`
`

`

`Reviewer: Margaret E. Brewer, PhD.
`
`NDA No. 21,660
`
`was less toxic in tumor—bearing mice as measured by MTDS and LDSD. The LD50 was calculated to be 47 and
`30mg/kg/d for ABl-OO'I and Taxol, respectively. Antitumor activity of ABI-007 was similar to that of Taxol in some
`of these sudies at these dose levels; in other studies, antiturnor of ABI-007 was superior to that of Taxol. In a
`different study, the binding of ABI-007 to albumin, microtubules, and endothelial cells appeared to be superior to
`that of Taxol.
`
`C. Nonclinical Safety Issues Relevant to Clinical Use
`The incidence of Grade 3 sensory neuropathy was greater in Abraxane-treated patients in the Phase 3 comparative
`study of Abraxane vs. Taxol with lower frequency of neutropenia with Abraxane. Neurotoxicity appears to follow a
`similar pattern preclinically, although dog studies were complicated by the immunological reaction of the human
`serum albumin component of ABl-OO'I. Differences in neurotoxicity between Abraxane and Taxol therapy have
`been addressed clinically. Testicular atrophy/degeneration was observed in multiple studies with Abraxane.
`Abraxane is embryotoxic and fetotoxic to rats at doses of 0.05 the maximum daily recommended human dose on a
`mng basis. These findings have been addressed in the label. A study was submitted which iustified the increase in
`shelf—life specification of
`—-
`impurity
`—-
`from
`-_._.
`
`Ill.
`
`Administrative
`
`A. Reviewer signature:
`
`B. Supervisor Signature: Concurrence -
`
`
`
`Non-Concurrence -
`
`(sec memo attached)
`
`C. cc: list:
`
`

`

`Reviewer: Margaret E. Brower, PhD.
`
`NDA No. 21,660
`
`2. 6 PHARMACOLOGY/TOXICOLOGY RE VIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number: 21,660
`Review number: 1
`
`Sequence numberldateltype of submission:
`Information to sponsor: Yes (X ) No ( )
`Sponsor: American BioScience, Inc, Santa Monica, CA
`Manufacturer for drug substance :
`
`Previous suppliers of oaclitaxel for ABI«007:
`a.
`.__l
`
`Current supplier of paclitaxel for ABl-007:
`.a
`(natural biosource, T. media)
`
`Sources of Human Serum Albumin HSA :
`
`—’
`
`Current supplier of Human Serum Albumin:
`
`Reviewer name: Margaret E. Brewer, PhD.
`Division name: Oncology
`HFD #: 150
`
`Review completion date: December 1, 2004
`
`Drug:
`
`Trade name: Abraxane (previous name: Capxol)
`Generic name: paclitaxel protein—bound particles for injectable suspension
`Code name: ABI-OO?
`'
`
`Chemical name: 5i}, ZO-epoxy—l, 2a, 4,7B, 10B, lSoc—hexahydroxytax-l l-en-9-one—4,
`benzoate- l 3Aester with (2'11, 3'S)—N-benzoylG-phenylisoserine
`CAS registry number: 33069-62-4
`Mole file number: N/A
`
`lO-diacctate—Z—
`
`Molecular formula/molecular weight: C41H51N014 /853.9l
`Structure:
`
`5H
`
`°
`
`2
`
`’1:
`H
`
`Relevant INDs/NDASIDMFS: [ND 55,974 IND ——:
`NDA ——~
`.ND55,974
`
`IND / DMF ——
`
`NDA 20262,
`
`Drug class: cytotoxic
`
`Intended clinical population:
`
`-’
`
`
`
`

`

`
`
`Reviewer: Margaret E. Brewer, PhD.
`
`NDA No. 21,660
`
`Clinical formulation:
`
`Dru roductf formulation com orients 50mL vial):
`
`
`
`_lrru~._
`Human serum albumin, USP
`900mg
`
`
`
`
`
`
`
`
`
`
`
`For administration, each vial is reconstituted with 20mL 0.9% Sodium Chloride Injection, USP, to give a suspension
`of fine particles containing 5mg paclitaxel/mL, pH
`‘-._
`
`Route of administration: iv, 30m infusion of 260mg/n12 q3w
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer from the sponsor‘s submission
`unless cited otherwise.
`
`Data reliance : Except as specifically identified below, all data and information discussed below and necessary for
`approval of NDA # 21,660 are owned by American Bioscience, Inc. or are data for which American Bioscienee, Inc.
`has obtained a written right of reference. Any information or data necessary for approval of NDA a 21,660 that
`American Bioscience, Inc. does not own or have a written right to reference constitutes one of the following: (1)
`published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as described in the drug’s
`approved labeling. Any data or information described or referenced below from a previously approved application
`that American Bioscience, Inc. does not own (or from FDA reviews or summaries of a previously approved
`application) is for descriptive purposes only and is not relied upon for approval of NBA # 21,660.
`
`Studies reviewed within this submission:
`Pharmacology
`
`E691
`
`A0692
`
`A0693
`
`A0694
`
`SRI-LIF-97-
`171-90244
`
`BIO—EL—l
`
`
`Anticancer efficacy evaluation of American Bioscience compound ABI-007 against HT29 human
`tumor xenograft in athymic nude mice
`
`Comparison of effects of ABI-007 and Taxol in athymic nude mice with PC-3 human prostate
`tumor xeno_rafts
`Comparison of effects of ABI‘007 and Taxol in athymic nude mice with NCI-H522 lung tumor
`xenografts
`Anticancer efficacy evaluation of American Biosciences compound ABI—007, ABI—007HC and
`ABl-007LC against SK-OV-3 human ovarian tumor xenografi in ath
`ic nude mice
`Toxicity determination and efficacy studies of VivoRx compounds Capxol VR—3 and Capxol VR-4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Binding of paclitaxel to albumin, microtubules, and cells. Inhibition of binding by Cremophor-EL
`and com arative analysis of ARI-001T vs Taxol
`
`Pharmacokinetics
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Distribution of Fifi-labelled AB1-007 and Taxol in tumor bearing mice
`Distibution of[ H]—1abelled ABI-OO? and Taxol in female tumor bearin_ mice
`Blood kinetics and tissue distribution ofpaclitaxel following a single intravenous dose ofCapxol in
`the rat
`
`Pharmacokinetics and metabolism of H-ABI-OO?‘ and Taxol following a single intravenous dose in
`the rat
`
`A590. l.2
`91096001
`
`P0202002
`
`NPOO 1 106
`
`
`
`
`
`
`
`
`
`
`Blood kinetics study on 3 formulations of ABI-007 following a single intravenous dose in rabbits at
`SOmg/kg
`
`
`
`P0297003
`Blood kinetics of H—paclitaxel derived radioactivity following single intravenous doses in the rat at
`
`
`9, 30, 90 and lZ-ing/kg
`
` i'0303014
`Blood kinetics study comparing 3 biosources ofpaclitaxel in ABl—007 following a single
`intravenous dose in the rat at 50mg/l-tg
`
`
`
`
`

`

`Reviewer: Margaret E. Brower, PhD.
`
`NDA No. 21,660
`
`Toxicology
`
`Pit-0002
`
`PR—0003
`
`PR—0004
`PR-0007
`
`P0397006
`
`Pilot study of myelosuppression in rats with Capxol and Taxol following a single intravenous
`
`administration
`
`Determination of the LDso in mice for Capxol and Taxol following a single intravenous
`administration
`
`LDSD of ABI-OO'." and Taxol following multi . le iv administrations
`Investigation of dose response to myelosuppression in rats following intravenous administration of
`Capxol
`Determination of the toxicity in rats of Capxol and Taxol following a single intravenous
`administration
`
`
`
`study of Ca uxol in bea _le dogs
`Fourteen day acute intavenous toxicit
`P0897001
`Fourteen day acute intavenous toxicity study of Ca mo] in bea
`P0997006
`LY‘CHRON— Toxicity of systemic delivery of nanoparticle paclitaxel (ABI-OO'I‘) in swine
`001
`
`Reproductive Toxicology
`
`
`Intravenous develomental toxicity study of aclitaxel in rats
`
`Intravenous fertility and general reproduction toxicity of paclitaxel in male rats
`
`4701-001
`4701-002
`
`Special Toxicology
`
`P0603001
`
`Comparison of the 28-day toxicity of ABI-OO'I‘ following a single intravenous dose of drug product containing usual and elevated levels of,
`
`f‘"
`
`in rats
`
`Studies not reviewed within this submission:
`
`t
`
`Drug History:
`Abraxane is composed of a Crcmophor-free formulation of the approved cytotoxic agent paclitaxel formulated in
`human serum albumin. Paclitaxel promotes the assembly of microtubules from tubulin dimers and stabilizes
`microtubules by preventing depolyrnerization. The sponsors of Abraxane (also known as Capxol and ABl-007) have
`used multiple suppliers ofpaclitaxel, as well as human serum albumin since the [ND was originally discussed and
`submitted in 1998. Three biosource materials have been studied during development of Abraxane:
`"“
`'
`---'
`nd natural biosource. Phase "l studies were conducted using the natural biosource, Taxus
`media, manufactured by
`'— _ . which is to be used commercially. The
`"" drug product was
`also used as the source of several Phase 1 and Phase 2 studies. Three other sources ofpaclitaxel have been used in
`the development of the drug product:
`
`1- Paclitaxel produced at '
`and several Phase I an Phase 2 studies.
`
`-"
`
`V
`
`.
`
`.
`
`was used in pre—clinical
`
`2-
`
`..._
`-'
`
`was the supplier ofpaclitaxel in the original IND (IND 55,974) manufactured
`and used in Phase 1 clinical studies and pro-clinical studies.
`
`

`

`Reviewer: Margaret E. Brewer, PhD.
`
`NDA No. 21,660
`
`3-
`
`. provided a single lot of technical grade paclitaxel used in exploratory
`pharmacodynamics studies in mice.
`
`n
`
`utilized.
`
`Sources of the (HSA) human serum albumin have also changed during the development of Abraxane. The
`HSA supplied by
`""
`""‘
`
`_
`
`kcurrent supplier) were subsequently
`
`Pro-clinical pharmacokinetic studies comparing the dilTering biosource formulations and differing paclitaxel to HSA
`ratios have indicated only minor changes which would not significantly impact the comparative toxicity of the drug.
`
`Mam nut
`on antenna—Em
`
`

`

`Reviewer: Margaret E. Brewer, PhD.
`
`NDA N0. 21,660
`
`2.6.2
`
`PHARMACOLOGY:
`
`2.6.2.1 Brief summary
`The efficacy of Taxol and ABI-OO? were compared as to their effects on tumor free survival and tumor
`growth rate for HT29 colon tumor, PC—3 prostate tumor, NCI-HSZZ lung tumor, SK-OV—3 ovarian tumor and MX-l
`mammary tumor (See table below). ABI—007 was less toxic in tumor-bearing mice as measured by MTDs and L050.
`The LDSQ was calculated to be 47 and 30mg/kg/d for ABI—007 and Taxol, respectively. Antitumor activity of ABI-
`007 was similar to that of Taxol in some of these sudies at these dose levels; in other studies, antitumor of ABl-007
`
`was superior to that of Taxol. In a different study, the binding of ABI—OO7 to albumin, microtubules, and endothelial
`cells appeared to be superior to that of Taxol.
`
`2.6.2.2 Primary pharmacodynamics:
`
`Multiple iv dose — efficacy of
`increasing doses of ABl-007 or
`Taxol
`
`Multiple iv dose — efficacy of
`increasing doses of ABl-007 or
`Taxol
`
`MTD: 20mg/kg ABl-007, 13.4mg/kg
`Taxol. Antitutnor activity of ABI-007
`superior at s-ecified doses
`MTD: 20mg/kg ABl-007, 13.4mg/kg
`Taxol. Antitumor activity of ABl-007
`similar to Taxol
`
`Multiple iv dose — efficacy of
`increasing doses of ABl-007 or
`Taxol
`
`MTD: 20mgfkg ABl-OO7, 13.4mg/kg
`Taxol. High rate of response to both
`ABl-007 and Taxol
`
`Studytt
`A069.1
`
`A0692
`
`A0693
`
`A069.4
`
`Animal model
`NCr-nu mice w!
`HT29 human colon
`tumor
`
`NCr-nu mice wf
`PC—3 human
`
`prostate tumors
`NCr-nu mice w/
`NCI-H522 human
`
`lung tumors
`NCr-nu mice w! SK-
`OV-3 human
`ovarian tumors
`
`Control: no survival after 47d
`
`SRI—LIF-97-
`17130242
`
`NCr-nu mice w/
`MX—l human
`mammary tumors
`
`Multiple iv dose — efficacy of
`increasing doses of ABl-OO')’ or
`Taxoi
`
`Multiple iv dose — efficacy of
`increasing doses of 3 ABI-007
`formulations or Taxol
`
`MTD: 20mgfkg AB1~OO7, 13.4mg/kg
`Taxol. All 3 ABI-007 formulations
`
`superior to Taxol
`(formulations differed in ratio of
`aclitaxel to albumin)
`Tumor-free survival for ABl-007
`
`treated mice superior
`MTD differs for this study
`ABl-007 (45mg/kg/d) [00% survival
`to 103d
`
`Taxol (30mg/kg/d) 40% survival to
`103d
`
`Several pharmacology studies were performed to investigate efficacy. These studies indicated that tumor
`accumulation of ABI-007 was higher than that of 'l‘axol. Mice administered paclitaxel formulated as ABI-OO?
`exhibited decreased plasma AUC and increased tumor AUC compared to mice administered paclitaxel formulated as
`Taxol.
`
`Study # BlO-EL-l Binding of paclitaxel to albumin, microtubules, and cells. Inhibition of binding by
`Cremophor—EL and comparative analysis of ABI-007 versus Taxol
`The binding of paclitaxel to human serum albumin, microtubules and endothelial cells were inhibited by clinical
`levels of Cremophor/ethanol. The binding of the ABLOO? formulation to human serum albumin, microtubules and
`endothelial cells appeared to be superior to that of Taxol.
`
`Mechanism of action: The mechanism of action of ABI—OO? can be described as the facilitation of active
`
`transport of albumin—bound paclitaxel into a tumor site by an albumin receptor. While targeting the vascular
`endothelium, the intratumoral concentration of the drug is increased by utilizing an amplification effect imparted by
`angiogenesis, resulting in increased efficacy white expecting to minimize exposure to normal tissue.
`
`Drug activity related to proposed indication: no specific data submitted preclinically
`
`2.6.2.3 Secondary pharmacodynamics No data submitted
`
`
`
`
`

`

`Reviewer: Margaret E. Brewer, PhD.
`
`NDA N0. 21,660
`
`2.6.2.4 SAFETY PHARMACOLOGY:
`
`Neurological effects: No safety pharmacology studies submitted
`
`Cardiovascular effects: No safety pharmacology studies submitted
`
`Pulmonary effects: No safety pharmacology studies submitted
`
`Renal effects:
`
`No safety pharmacology studies submitted
`
`Gastrointestinal effects: No safety pharmacology studies submitted
`
`Abuse liability: No safety pharmacology studies submitted
`
`Other: No safety pharmacology studies submitted
`
`2.6.2.5 Pharmacodynamic drug interactions No studies submitted
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY
`
`[See above summary]
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS:
`
`2.6.4.1 Brief summary
`Pre—clinical studies indicate that ABI-OO'.‘1 is similar to Taxol in several parameters. Metabolism and
`excretion are similar to that ofTaxol; excretion is primarily fecal and these drugs are largely eliminated within 48h
`ofdosing. However, ABl-007 exhibits a greater volume of distribution and longer half-life compared to Taxol.
`Distribution is rapid with highest tissue distribution in prostate, liver, seminal vesicles, lung, pancreas, spleen, GI
`and kidney; in a separate study, tissue concentration was highest in liver, testes and ovaries. In general, tissues with
`highest JH-ABI-Dffl derived radioactivity concentrations are involved in metabolism/excretion, contain a high
`proportion of dividing cells, or are highly perfused. Mice administered paclitaxel formulated as ABI-OO'J' exhibited
`decreased plasma AUC and increased tumor AUC compared to mice administered paclitaxel formulated as Taxol.
`Similar pharmacokinetics were exhibited for differing albuminzpaclitaxel ratios of ABI—007 and differing
`formulations using natural,
`-—-
`biosourcc for ABI-007. However, Since the
`natural biosource was utilized for Phase 3 studies and will be used commercially, it should be noted that this ABI-
`007 biosource exhibited a slightly higher systemic exposure, with an extended half-life compared to the
`~—
`__
`biosources. For this study, study authors indicate measurement of whole blood
`
`paclitaxel.
`
`2.6.4.2 Methods of Analysis
`[See individual study reviews]
`
`2.6.4.3 Absorption (incorporated in studies below)
`
`2.6.4.4 Distribution
`
`Study title: Blood kinetics and tissue distribution of paclitaxel following a single intravenous dose of Capxol
`in the rat
`
`Key Findings:
`- Rapid distribution ofJH-Capxol from blood to tissues
`- Tissue distribution highest: prostate, liver, seminal vesicles, lung, pancreas, spleen, GI, kidney
`' AUC 0.2.", 60% of total radioactivity are metabolites
`
`10
`
`

`

`
`
`Reviewer: Margaret E. Brewer, PhD.
`
`NDA N0. 2l,660
`
`Study no: P1096001
`1
`Volume #, and page #1 vol 2, p.
`Conducting laboratory and location:
`Date of study initiation: November l8, 1996
`GLP compliance: yes
`QA report: yes (X) no ( )
`~— , [portion of JH—Paclitaxel
`Drug, lot #, radiolabel, and % purity: 3H—Paclitaxel. lot #l24-l3 [-0023,
`formulated to 3H-Capitol], radiochemical purity _'
`onradiolabeled paclitaxel, lot 96091 l,
`.—
`Formulation/vehicle: diluted with 0.9% NaCl (Taxol vehicle not specified, although historically diluted with
`0.9%NaCL).
`
`Dosing:
`
`Speciesfstrain: rat/Sprague Dawley (males only)
`#lsex/group (main study): 10
`Satellite groups used for toxicokinetics: none
`Age: 7-8w
`Weight: not provided
`Doses in administered units: 5.lmg/kg Capxol (84.6uCi/g); 4.9mg/kg Taxol (radiolabeled; details
`unspecified)
`Specific activity: 62,909dpm/ug (3H-paclitaxel in dosing solution)
`Route, form, volume, and infusion rate: iv, dose volume 1.67mng
`Method of Analysis: LC/MS
`Blood collection: 2, 5, l5, 30m, 1, 2, 3, 4, 5, 6, 8, 12, 24h
`
`Total radioactivity and parent compound level following administration of Capxol l bi-phasically over 5h post-dose
`followed by linearl to 24h. AUC 0,24}, exposure for parent paclitaxel was 60% of total radioactivity due to
`metabolism. The following tissues exhibited the highest total radiolabel distribution (up to 5X paclitaxel blood
`level): prostate, liver, seminal vesicles, lung, pancreas, spleen, GI tract, kidney (See Sponsor's graph below). With
`exception of pancreas, tissues with highest concentrations are involved in metabolism/excretion (liver, GI, kidney),
`contain a high proportion of dividing cells (seminal vesicles, prostate), or are highly perfused (lung and spleen).
`
`Blood levels following Capxol administration were lower than following similar Taxol dose, indicating more rapid
`distribution out of blood (2m post-dose sample). Similar pattern of metabolism were observed for both Capxol and
`Taxol. However, the rate of metabolism was significantly slower for Capxol as 44% of blood reactivity remains as
`paclitaxel 24h post-dose, compared to 22.4% for Taxol. Predominantly fecal excretion was exhibited with both
`drugs, with only minimal excretion via urine.
`
`Paclitaxel
`concentration
`
`AUCo.24(ugeq-hrme)
`
`Cmaxtug eq/mL)
`
`
`
`_.
`_.
`
`|—.
`_0-2
`
`Tissue radioactivity levels were higher 24h following Capxol administration as compared to Taxol administration
`for 9 of 14 assayed tissues. Tissue/blood ratios were higher for Capxol-dosed animals with lower paclitaxel-blood
`levels, indicating rapid distribution of Capxol from blood to tissues.
`
`
`
`11
`
`
`
`

`

`Reviewer: Margaret E. Brower, PhD.
`
`NDA N0. 21,660
`
`”I
`
`'l'iSér: [oldioactivity Levels Esprcswé 23 ppm Helium! EqLivnlcnis
`24 Hours Following a Single intravenous Administration of
`“‘i'E-l‘axaf‘” rt 4 9 my’kg or 3li-Ca_mca:.l’~"‘- at S ': map-”Kg
`i
`ll| l
`
`“-4;wa r_
`
`
`
`Summary:
`Total radioactivity of ABl-007 decreased biphasically over Sh post-dose followed by linear decrease to 24h.
`The distribution of 3l—l—Capxol from blood to tissues appears to be rapid; tissue distribution was highest in prostate,
`liver, seminal vesicles, lung, pancreas, spleen, GI and kidney. Metabolites comprised 60% ofCapxol AUC 9.2.".
`total
`radioactivity. Metabolism was slower for 3H—Capxol as compared to 3H-Taxol, with 44% of blood radioactivity
`remaining as paclitaxel 24h post-dose, compared to 22% for 1H—Taxol.
`
`2.6.4.5 Metabolism (Studies grouped as Metabolism/Excretion)
`2.6.4.6 Excretion
`
`Blood kinetics of 3H-paclitaxel derived radioactivity following single intravenous doses of
`Study title:
`Capitol in the rat at 9. 30, 90, and 120mg/kg
`
`Note: Doses administered to animals varied from doses indicated in study title (see below).
`
`Key study findings:
`' JH—ABI-007 slowly metabolized in vivo; 7-l9% unchanged at 24h
`' Exposure increases disproportionately with increasing dose
`
`--'
`
`Study no: P0297003
`Volume #, and page #: Vol 2, p, 1; Electronic submission
`Conducting laboratory and location:
`Date of study initiation: April 2, I997
`GLP compliance: yes
`QA report: yes (X) n0( )
`Drug, lot #, radiolabel, and “/o purity:
`. purity);
`._..
`purity), 127-097-0053 '
`aH-paclitzixel, lot?! : 124-131-0028 (' _
`nonradiolabeled paclitaxel: 101%? 960911. ' - purity; nonradiolabeled Capxol: lot# A5»05, purity not
`provided
`JHACapxol batches # A4-75, A5-03 formulated from above paclitaxel; noted purity
`Dose/group (5M): paclitaxel doses: 9.], 26.4, 1 16.7, 148.1mg/kg
`radioactive dose: 38.6, 35.6, 39.3, 36.8uCi respectively
`Blood sample collection: 2, 5, 15m, 0.5, l, 2, 3, 4, 5, 6, 8, 12, 24h post—dose
`
`.—
`
`24h HPLC analysis indicated 7-l9% of blood radioactivity as unchanged paclitaxel, indicating a slow rate of
`metabolism. Exposure increases disproportionately with increasing dose, suggesting saturation ofclearance.
`
`12
`
`

`

`
`
`
`
`Reviewer: Margaret E. Brewer, PhD.
`
`NDA N0. 21,660
`
`
`
`Study title:
`(lose in the rat
`
`Pharmacokinetics and metabolism of 3H-ABl-007 and Taxol following a single intravenous
`
`Key study findings:
`- Highest tissue distribution in liver, testes and ovaries, JH'ABI'OOT; lung, liver, testes, 3H—Taxol
`~ Primary route of excretion: feces
`- 3H-ABl-OO'F excreted in urine as metabolite, feces as paclitaxel
`
`Study no: P0202002
`Volume #, and page #2 Vol 2, p. 1; Electronic submission March, 2004
`Conducting laboratory and location:
`_....
`Date of study initiation: July 24, 2002
`GLP compliance: yes
`QA report: yes (X) no ( )
`Drug, lot #, radiolabel, and "/9 purity: 3l-l-ABI—OO'.", 3H-paclitaxel (lot# 424—218-003, 424-242-0147)
`Non-radiolabcled paclitaxel (10t#15359/N) manufactured by _" , purity final drug "‘
`3l’l—Taxol as control
`
`Formulation/vehicle: reconstituted with 0.9% NaCl
`
`Dosing:
`Specieslstrain: rat/Sprague Dawley
`#lsexlgroup (main study): 5 (2 misdosed animals replaced)
`Satellite groups used for toxicokinetics or recovery: none
`Age: 7—8w M; 11-12w F
`Weight: 182-223g
`Doses in administered units: jH-Taxol: 5.93mg/kg M, 5.98mg/kg F; 3H-r‘lBl-L‘lOT: 7.69mg/kg M, 7.79mg/kg F
`Route, volume, and infusion rate: iv, dose volume 5ml/kg, final diluted concentration: 1mg paclitaxel/mL
`Method of Analysis: LC/MS (measured 3l-l-paclitaxel derived from ABl-OO'I' and Taxol)
`Urine/fecal sample collection: 0—4, 4-8, 8-12, 12-24, 24-36, 36-48, 43-72, 72-96, 96-120h following dosing
`
`The highest concentration of 3l-l-ABI-DO? derived radioactivity was found in the liver, testes and ovaries;
`distribution was similar in males and females (See Sponsor's graphs below).
`In comparison, the highest
`concentration of 3H~Taxol derived radioactivity was found in the lung, liver and testes. As with previous studies, the
`primary route of excretion was the feces; fecal excretion was 82 and 78% of administered dose of ABI—OO'I‘ in males
`and females, respectively, between 8-120h (compared to 77 and 75% in Taxol-treated males and females for the
`same time interval). The majority of this fecal radioactivity was excreted within 48h following dosing. Comparative
`excretion in the urine was 8. 10% and 12.45% in males (between 4 and 120h) and females (between 0 and 1201])
`administered Taxol, respectively, and 9.51% and {4.07% in males and females administered ABl—007, respectively
`for the same time intervals Little radioactivity was observed in tissue samples afier 5d post-dose.
`
`13
`
`

`

`
`
`Reviewer: Margaret E. Brewer, PhD.
`
`NDA NO. 21,660
`
`res-Tn m. "IHsilx‘Iu-r R. rim-s u |A=.':u- I133.
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`
`2.6.4.7 Pharmacokinetic drug interactions No studies submitted
`
`2.6.4.8 Other Pharmacokinetic Studies
`
`Blood kinetics study comparing three biosources of paclitaxel in ABI-007 following a single
`Study title:
`intravenous dose in the rat at 50mg/kg
`Lime: Natural bi0§ggr_ce_t_o_b§Ltil_i_zed commercialLy
`
`Key study findings:
`' Similar pharmacokinetics for paclitaxel fi'om 3 different biosources
`- Exposure ofpaclitaxel slightly higher for natural biosource
`-Termina] [112 ofpaclitaxcl extended w/ natural biosouree
`Cm“ of paclttaxel slightly higher for -
`biosource
`
`14
`
`

`

`
`
`Reviewer: Margaret E. Brower, PhD.
`
`NDA N0. 21,660
`
`
`
`Study no: P0303014
`Volume #, and page #: Vol 2, p. 1, Electronic submission: March, 2004
`Conducting laboratory and location:
`Date of study initiation: April 21, 2003
`GLP compliance: yes
`)
`QA report: yes (X) no (
`Drug, lot #, radiolabel, and % purity: Three ABl—007 paclitaxel formulations, manufactured using differing
`biosource material:
`
`#C018-001(Capxol) biosource from ' —
`#Cl99-004, biosource frorr'
`"'
`#C102—005, biosource from —-
`
`Formulationfvehiele: diluted with 0.9% NaCl
`
`Dosing:
`
`Species/strain: rat/Sprague Dawley (males only)
`#lsex/group (main study): 8 (2 animals replaced due to misdosing)
`Satellite groups used for toxicokinetics or recovery: none
`Age: 8-9w
`Weight: 254-280g
`Doses in administered units: 50mg/kg
`Route, form, volume, and infusion rate: iv, dose volume Sml/lrg, final diluted concentration: 10mg
`paclitaxel/mL
`Method of Analysis: LC/MS
`Blood collection: 5, 15, 30m, 1, 2, 4, 8, 24, 48, 72h
`
`
`
`
`
`ABI—OO?
`Dose (mg/kg)
`
`biosource
`
`Terminal tug
`(h)
`
`
`
`Cmax (ng/mL)
`(normalized
`value)
`
`
`
`AUC inf
`AUC last
`{rig x h/mL)
`(ng x h/mL)
`
`
`(normalized
`(normalized
`
`
`value)
`value)
`
`48122
`48022
`(951}
`(953)
`
`
`50164
`50072
`6.1
`
`
`(1013)
`
`
`
`52046
`51915
`
`
`(1027)
`(1024)
`
`
`
`
`
`
`
`(1012]
`
`7.8
`
`9.6
`
`I
`
`I
`l_(natural)
`
`
`
`The 3 formulations appeared to have similar pharmacokinetic parameters. Normalized AUC indicate that exposure
`was slightly higher with the natural biosource and lower with the
`-—'
`biosource. Terminal 0