`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-660
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW! S 2
`
`

`

`CLINICAL PHARMACOLOGYAND BIOPHARMACEUTICS REVIEW
`
`NDA:
`
`Brand Name:
`
`Generic Name:
`
`Indication:
`
`Dosage Form:
`
`Strength:
`
`21,660
`
`Abraxane
`
`Paclitaxel protein-bound particles
`
`for
`
`injectable
`
`suspension (albumin bound)
`
`100 mg of paclitaxel and 900 mg of human albumin
`
`Each milliliter
`
`(ml) of reconstituted suspension
`
`contains 5 mg paclitaxel
`
`Route of Administration:
`
`IV Infusion
`
`Dosage and administration:
`
`260 mg/m?‘ over 30 minutes every 3 weeks
`
`Applicant:
`
`OCPB Division:
`
`OND Division:
`
`Submission Date:
`
`American Bioscience, Inc.
`
`Santa Monica, CA 90403
`
`Division of Pharmaceutical Evaluation I (HFD—860)
`
`Division of Oncology Drug Products (HFD-ISO)
`
`l9—MAR-2004; 21-JUN—2004;
`
`7-IUL-2004;
`
`22-
`
`J UL—2004; ll-OCT—2004
`
`Primary Reviewer:
`
`Angela Yuxin Men, M.D., PhD.
`
`
`
`Acting Team Leader:
`
`Brian Booth, PhD.
`
`Pharmacometrics Team Leader:
`
`Jogarao Gobburu, PhD.
`
`

`

`
`
`TABLE OF CONTENTS
`
`PAGE NUMBER
`
`1 2
`
`18
`
`19
`
`20
`
`22
`
`24
`
`33
`
`ITEM
`
`Header
`
`Table of Contents
`
`I. Executive Summary
`
`A. Recommendations
`
`B. Phase IV Commitments
`
`C. Summary of Important CPB Findings
`
`[1. Question—Based Review
`
`A. General Attributes of the Drug
`
`B. General Clinical Pharmacology
`
`C. Intrinsic Factors
`
`D. Extrinsic Factors
`
`E. General Biopharmaccutics
`
`F. Analytical Section
`
`III. Detailed Labeling Recommendations
`
`IV. Appendices
`
`A.
`
`Proposed Package Insert (Original)
`
`B.
`
`Individual Study Review
`
`D. Cover Sheet and OCPB Filing/Review Form
`
`

`

`
`
`I
`
`Executive Summary
`
`The applicant submitted the original NDA 21-660, Abraxane, seeking marketing approval
`for the use of Abraxane in patients with metastatic breast cancer through the 505(b)(2)
`approach using Taxol® as a reference drug.
`
`is developed with the
`It
`Abraxane is a Cremophor—free formulation of paclitaxel.
`objective of eliminating Cremophor-EL and alcohol from Taxol
`to overcome some
`problems associated with these solvents,
`such as hypersensitivity. The clinical
`pharmacology section contains 4 study reports (CAOOS—O, DM97-123, CA012-0, and
`CA008-0) in patients with non--hematologic malignancies/solid tumor/metastatic breast
`cancer. In summary, pharmacokinetic (PK) studies were conducted1n 65 cancer patients
`aged 33 to 83 years old Patients were dosed from 80 to 375 mg/mz. Exposure increased
`linearly with doses between 80 to 375 mg/mz. Compared to Taxol, Abraxane showed
`higher total clearance (43%) and larger volume of distribution (53%). The terminal half—
`life, about 21 hours, was identical for Abraxane and Taxol The applicant did not study
`the safety and pharmacokinetics of Abraxane1n hepatic impaired patients In the Phase 3
`comparison study, 260 mg/m2 Abraxane was more efficacious than 175 mg/m2 Taxol.
`Abraxane demonstrated significantly higher
`reconciled target
`lesion response rate
`compared to Taxol. Abraxane did not require any pre—medication for hypersensitivity and
`there were no severe hypersensitivity reactions observed for Abraxane. This review
`evaluates the submitted data and provides recommendations on the labeling.
`
`A. Recommendations '
`
`The Office of Clinical Pharmacology and Biopharmaceutics (OCPB) finds the submitted
`data in NDA 21—660 for Abraxane acceptable, with some revisions to the applicant’s
`proposed label (please refer to Section III on page 24).
`
`B. Phase IV Commitment
`
`The applicant should evaluate Abraxane safety and pharmacokinetics in subjects with
`hepatic impairment, to allow the determination of dosing adjustment for this population.
`
`C. Summary of Important Clinical Pharmacology and Biopharmaceutics
`Findings
`
`Abraxanc (paclitaxel protein-bound particles for injectable suspension) is an albumin
`bound paclitaxel, which is
`free of Cremophor—EL solvents. The active ingredient,
`paclitaxel,
`is the same as Taxol. Pharmacokinetic parameters of total paclitaxel were
`determined in Phase 1, 2 and 3 studies after intravenous infusion of Abraxane over 30—
`and 180- minutes in cancer patients at doses of 80’375 mg/mz. The maximal tolerated
`dose (MTD) of Abraxane was determined to be 300 mg/mz, which was about 50% higher
`than the MTD for Taxol. Linear pharmacokinetics (PK) of Abraxane were observed
`
`
`
`

`

`between 80 to 375 mg/rnz. The total clearance of Abraxane was 15 L/hrfm2 and the
`volume of distribution was 632 Umz. The total clearance and volume of distribution of
`
`paclitaxel were higher when administered as Abraxane compared to Taxol. The terminal
`half—life of 2 l—hour was the same as Taxol. Urinary excretion of Abraxane accounted for
`<6% of paclitaxel and the renal clearance was 0.16 to 1-08 Li'hr/m2 which indicates that
`extra-renal elimination was extensive. Fecal excretion accounted for 22% of total dose.
`
`Paclitaxel accounted for 3% and its metabolite, 60t—hydroxypaclitaxel, 18%.
`
`In the Phase 3 study, Abraxane 260 mg/m2 was more efficacious than Taxol 175 mg/m2
`in the treatment of patients with breast cancer. Patients with metastatic breast cancer who
`received Abraxane demonstrated significantly higher Reconciled Target Lesion Response
`Rate (22% vs 1 1%, P = 0.003). Unlike Taxol, without any pro-medication, there were no
`severe hypersensitivity reactions observed for Abraxane. In the Phase 3 comparison of
`Abraxane versus Taxoi, patients treated with Abraxane experienced less neutropenia
`despite a 49% higher dose of paclitaxel. However, compared to Taxol, sensory
`neuropathy was more common in patients treated with Abraxane.
`
`__—_______—_
`Angela Yuxin Men, PhD.
`Reviewer
`Division of Pharmaceutical Evaluation I
`
`Date:
`
`Office of Clinical Pharmacology and Biopharmaceutics
`
`Brian Booth, PhD.
`
`Acting Team Leader
`Division of Pharmaceutical Evaluation I
`
`Office of Clinical Pharmacology and Biopharmaceutics
`
`Date:
`
`
`
`

`

`II. Question-Based Review
`
`A. General attributes of the drug
`
`What are the highlights of the chemistry properties of the drug substance, and the
`formulation of the drug product as they relate to clinical pharmacology and
`biopharmaceutics review?
`
`Abraxane (paclitaxel protein—bound particles for injectable suspension) is an albumin
`bound form of paclitaxel (Figure 1), which has anti-tumor activity. Paclitaxel is obtained
`as a natural product from Taxus media and its structure is shown in Figure 2_
`
`
`
`Protein (Albumin)
`
`Nanoparlicie Albumin Eouno‘:
`Protein-engineered Nanoparticies
`
`Of Water-insoluble Drugs
`
`Drug {paclitaxen
`
`Figure 1 Structure of Abraxane (NanOparticle Albumin-bound Paelitaxel)
`
`
`
`Figure 2 Chemical Structure of paclitaxel
`
`Formulation
`
`its negatively charged albumin prevents
`Abraxane is a cremophor—free formulation.
`paclitaxel nanoparticle agglomeration. Abraxanc is supplied as a white to yellow, sterile,
`lyophilized powder. Each single-use vial
`contains
`100 mg of paclitaxel
`and
`
`

`

`
`
`is reconstituted with 20 mL of
`approximately 900 mg of human albumin. Each vial
`Sodium Chloride Injection, USP, to produce a suspension containing 5 mg paclitaxel/mL.
`
`What are the proposed mechanism(s) ofaction and therapeutic indication(s)?
`
`Proposed Mechanisms of Action
`
`Abraxane’s antitumor activity is mediated through paclitaxel. Using proprietary
`nanoparticle technology, Abraxane combines the active drug paclitaxel with a natural
`protein called albumin into a nanoparticle 1/100th the size of a red blood cell, avoiding
`the need of a solvent for paclitaxel. Paclitaxel is an antimicrotubule agent that promotes
`the assembly of microtubules from tubulin dimers and stabilizes microtubules by
`preventing depolyrnerization. This stability results in the inhibition of the normal
`dynamic reorganization of the microtubule network that is essential for vital interphase
`and mitotic cellular functions.
`In addition, paclitaxel
`induces abnormal arrays or
`“bundles” of microtubules throughout the cell cycle and multiple asters of microtubules
`during mitosis. In animal studies, administration of Abraxane resulted in higher intra-
`tumor and lower normal
`tissue conCentrations of paclitaxel than Cremophor (CrEL)-
`based paclitaxel.
`
`Indication
`
`Abraxane is indicated for the treatment of breast cancer after failure of combination
`
`relapse within 6 months of adjuvant
`chemotherapy for metastatic disease or
`chemotherapy. Prior therapy should have included an anthracycline unless clinically
`contraindicated.
`
`What are the proposed dosage(s) and route(s) of administration?
`
`For metastatic breast cancer patients, the recommended dose of Abraxane is 260 rng/mz,
`administered intravenously over 30 minutes once every 3 weeks.
`
`Hepatic Impairment: The appropriate dose of Abraxane for patients with bilirubin
`greater than 1.5 mg/dL is not known.
`
`The incidence of severe neutropenia following Abraxane was about 9%. Patients who
`experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe
`sensory neuropathy during Abraxane therapy should have the dosage reduced by 20% for
`subsequent courses of Abraxane.
`
`B. General Clinical Pharmacology
`
`What are the design features of the clinical pharmacology and clinical studies used to
`support dosing or claims?
`
`
`
`
`
`

`

`The overall schematic of Abraxane clinical studies is listed in Table 1. Per suggestion
`from FDA, the applicant conducted Study CAOOS—O later to compare PK of Abraxane and
`Taxol. Each PK study design was descn'bed.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`APPEARS THIS WAY
`0“ ORIGINAL
`
`
`
`

`

`Table 1 Schematic of Abraxane Clinical Program
`
`MIMI CIInIcII Program
`
`Uncontrolled smug In
`comma Study In
`Support of Proposed
`Proposad Indicafion &
`Inflaxflon
`Dom Bahama
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`PK; unharmed non-heminlng‘c
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`
`n = 30
`
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`
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`*1 Summary rapom pmfldod (Item 3)
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`|
`
`

`

`
`
`Pivotal Study:
`
`Study CA012-0
`
`This was a phase 3 multi-center, open——label, controlled randomized study in patients
`with metastatic breast cancer. Two hundred and twenty-nine patients received 260 rug/m2
`Abraxane IV over 30 minutes and 225 patients received Taxol 175 mg/m2 as a 3-hour
`infusion every three weeks. The primary objective of this clinical trial was to compare the
`efficacy and safety between Abraxane and Taxol.
`
`A subgroup of twelve non—randomized patients, who received 260 mg/m2 Abraxane, was
`enrolled for PK study during the first treatment cycle. Blood, urine, and feces samples
`were collected and analyzed by HPLC/MS for total paclitaxel and two metabolites, 601-
`hydroxypaclitaxel and 3’—p-hydroxypaclitaxel. The biodisposition and elimination of total
`paclitaxel (Abraxane) were investigated in this study.
`
`Supportive Studies:
`
`L
`
`Study CAOOS—O
`
`This was a phase 1 study to evaluate the safety, tolerability, and efficacy of Abraxane
`administered IV over 30 minutes once weekly for three weeks, followed by a week of rest
`in patients with advanced non—hematological malignancies.
`
`u
`
`The study was a single center, open—label, out-patient study, which consists of three
`phases: baseline, treatment, and 3—month follow u . A subgroup of twenty-three patients,
`who received Abraxane at doses of 80—200 mg/m , was selected for the PK study during
`the first dosing cycle. Total paclitaxel PK parameters were calculated.
`
`;
`
`Study DM97-123
`
`This was an open—label, dose—escalating study to determine the safety, tolerability, and
`PK of Abraxane in patients with solid tumors/breast cancer Sixteen of the nineteen
`enrolled patients participated1n this PK study. Three patients received 135 mglm2 over a
`3—hour infusion and the other patients received Abraxane, at dosages that ranged from
`135 to 375 mg/mz, as a 30—minute infusion once every three weeks. The maximal
`tolerated dose (MTD) was defined as the dosage level below the dosage resulting in >
`Grade 2 nonniyelosuppressive toxicity or > Grade 3 myelotoxicity in at least 2 of 6
`patients. Total paclitaxel PK for a 3»hour and 30-minute infusion were investigated.
`
`3L-
`
`Study CAOOS—O
`
`
`
`

`

`This was a phase 1, multi-center, open-label, controlled randomized comparative PK
`study comparing Abraxane (260 mg/m2 over 30 minutes) and Taxol (175 mg/m2 over 3
`hours) in patients with advanced solid tumors.
`
`Twenty-six patients were randomly assigned to receive either Abraxane 260 mg/m2 over
`30 minutes (11:14) or Taxol 175 mg/m2 over 3 hours (n=12). Whole blood samples were
`collected to measure the PK of total paclitaxel
`from the first dose cycle. The PK
`parameters of Abraxane and Taxol were obtained.
`
`What are the effectiveness and safety endpoints?
`
`Effectiveness Endpoints
`
`Two types of responses were assessed according to RECIST guidelines: target lesion and
`overall responses (target and nontarget lesion), in which the continuation of a complete
`response (CR) and a partial response (PR) required reSponse duration 2 4 weeks.
`
`The primary efficacy endpoint was the percentage of patients who achieved confirmed
`complete or partial target lesion response. The assessment of target lesion response
`(TLRR) by the Cycle 6 visit was based on the Reconciled Response Assessment Dataset
`(recTLRR).
`
`Secondary efficacy endpoints for this study included the following:
`
`0
`
`0
`
`0
`
`0
`
`0
`0
`0
`
`0
`
`percentage of patients who achieved complete or partial overall response;
`
`time to disease progression (TTP);
`
`patient survival;
`
`percentage of patients who achieved each target lesion response of complete
`response (CR), partial response (PR), stable disease (SD), or progressive disease
`(PD);
`
`percentage of patients who achieved each overall response of CR, PR, SD, or PD;
`time to first complete or partial target lesion response;
`time to first complete or partial overall response;
`
`duration of complete or partial target lesion response;
`
`duration of complete or partial overall response;
`
`number of cycles of therapy to maximum target lesion response;
`
`number of cycles of therapy to maximum overall response;
`
`duration of CR, PR, or SD for target lesion response;
`duration of CR, PR, or SD for overall response; and
`
`'- QOL evaluated by changes from baseline in scores on the Eastern Cooperative
`Oncology Group (ECOG) (Zubrod) performance status scale, European
`Organization for Research and Treatment of Cancer Quality of Life Questionnaire
`(EORTC QLQ)-C30, and weight.
`
`10
`
`

`

`In the labeling, recTLRR is reported.
`
`Safeg Endpoints
`
`The safetyltolerability endpoints for this study included the following:
`o
`adverse events (AE5), serious adverse events (SAEs), and toxicities;
`
`hematology and clinical chemistry;
`-
`0 maximal degree of myelosuppression (nadir white blood cell [WBC] count and
`absolute neutrophil count [ANC]);
`patients with Grade 4 neutmpenia (defined as ANC < 0.5 x 109/L);
`time to recovery from Grade 4 neutropenia (defined as ANC 3 1.5 x 109/L), with
`and without growth factor treatment;
`
`-
`-
`
`0
`
`0
`0
`
`patient and physician assessments of peripheral neuropathy;
`
`vital signs (during dosing and follow-up);
`electrocardiogram (ECG).
`
`Are the active moieties in the plasma appropriateh; identified and measured to assess
`pharmacokinetic parameters?
`
`The plasma concentration of active moiety, free paclitaxel, was not measured. The
`concentrations of total paclitaxel of Abraxane and Taxol were measured in plasma/whole
`blood by LC/MS. The review of the assay can be found in Item 11 Section F.
`
`What are the characteristics of the exposure-response relationships ofAbraxane?
`
`There is no relationship between the paclitaxel exposure and clinical responses available
`because the PK and effectiveness results were not obtained from the same clinical study.
`
`Does this drug prolong the QT or QTc interval?
`
`The effect of Abraxane on QT/QTc interval prolongation was not addressed in the
`submission. It is reported that mean heart rate, QT, corrected QT (QTc) did not change
`after
`infusion of 175-200 rag/m2 paclitaxel over one hour with recommended
`antihistamine premedication in cancer patients.i
`
`What are the pharmacoklnetics (PK) characteristics of Abraxane and its major
`metabolite?
`
`Pivotal Study:
`
`Study CAOl2-0
`
`11
`
`
`
`
`
`

`

`60t-
`two metabolites,
`and its
`total paclitaxel
`concentrations of
`The plasma
`hydroxypaclitaxel and 3’-p-hydroxypaclitaxel, were measured in this study. Their
`concentration vs.
`time profiles are demonstrated in Figure 3. The PK parameters of
`paclitaxel are listed in Table 2.
`
`”3009.00
`
`m3: DO
`
`1363 C41
`
`Time (Hours)
`
`Figure 3 Paclitaxel, 60c-l1ydroxypaclitaxel and 3’-p-hydroxypaclitaxel Blood
`Concentration- Time Profiles (mean)
`
`Table 2 Paclitaxel PK Parameters in Study CA012-0
`
`Parameter"—
`(1..m infimll
`
`Mean
`
`%C\"
`
`I
`
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`
`
`
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`
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`
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`
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`
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`
`
`
`Paclitaxel displayed a multi—phasic disposition with total CL of ISL/h/mz, tug of 27 hours
`and V2 of 632 L/mz. Urinary elimination of paclitaxel only accounts for 4% of the CL“.
`
`the
`that
`The metabolite profiles follow a similar pattern to the parent drug except
`metabolite concentrations are substantially lower. The Tmax was delayed relative to that
`for parent drug due to the formation of metabolites.
`
`Total paclitaxel (Abraxane) had greater exposure than Get-hydroxypaclitaxel (22—fold)
`and 3’—p—hydroxypaclitaxel (59-fold). Urinary excretion of Abraxane only accounted for
`<6% of paclitaxel and the renal clearance was 0.16 to 1.08 L/hrx’m2 which indicates that
`extra-renal elimination was extensive. Fecal excretion accounted for 22% of total dose.
`
`Paclitaxel accounted for 3% and its metabolite, 60t—hydroxypaclitaxel 18%.
`
`12
`
`

`

`
`
`Study CA005 —0
`
`In this study, only the plasma concentration of total paclitaxel was measured. The mean
`paclitaxel concentration obtained from all patients vs. time profile is shown in Figure 4.
`The PK parameters of paclitaxel are shown in Table 3. Patient #7, who received 100
`mg/rn2 Abraxane over 30-minute, appears to be an outlier, which showed much higher
`concentrations at all time points. The disposition of paclitaxel showed a multi—phasic
`concentration—time profile. The PK of paclitaxel (Patient #7 excluded) over the dose
`range of 80—200 mg/rn2 appears linear when administered as a 30-minute infusion (Figure
`5).
`
`
`
`
`
`PaclitaxetConcentration(ngme;
`
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`
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`
`s3
`
`
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`
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`20
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`
`so
`
`50
`
`Figure 4 Total Paclitaxel (Abraxane) Concentration -Time Profiles for Patients
`Receiving 80 mgi’m2 through 200 mg/mz in Study CAOOS-O
`
`Table 3 Summary of Total Paclitaxel (Abraxane) PK Parameters (Mean, SD) in
`Study CA005—0
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`
`Study DM97-123
`
`The plasma concentration of total paclitaxel was measured in this study. The paclitaxel
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`listed in Table 4.
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`+ i35nghr€
`—fl— t35rmhn‘2 (30 11in)
`+ 200mm (36 win}
`
`4—375”ng (36 Min}
`
`+ @0me (30 win}
`
`Time (Hour)
`
`Figure 6 Mean Total Paclitaxel (Abraxane) Plasma/Whole Blood Concentration-
`Time Profiles in Study DM97-123
`
`Note: The Pharmacokinetic parameters for the 135 mgim2 dose were generated from plasma samples (n 2 3
`for 180 minute infusion; n = l for 30 minute infusion); for the 200 mg/m2 dose were generated from plasma
`([1 or I) and whole blood (n = 2); and for the 300 (n e 5) and 375 mgim2 dose (n = 4) were generated from
`whole blood samples.
`
`14
`
`

`

`
`
`Table 4 Summary of Paclitaxel (Abraxane) PK Parameters (mean, %CV) in Study
`DM97-123
`
`135*
`
`135*
`
`30
`
`(35)
`
`AUC.
`
`rug-hind.)
`
`5427
`35
`
`(29)
`
`(22)
`
`[1‘1
`
`t
`
`(hr)
`
`15‘?
`2
`'}
`
`63
`
`15)
`
`CL
`
`v2
`
`(Wm‘)
`
`(Um‘)
`
`
`
`
`
`
`27.2
`34
`
`21
`
`J,
`
`2
`
`3
`
`3
`
`8
`
`5
`
`(26)
`
`64
`
`4|
`(29
`36
`15
`‘PK parameters were generated from plasma samples; #PK parameters were generated from
`
`
`
`
`plasma(n=1) andwliole blood (n=2); +PK parameters were generated from whole blood samples.
`
`The biphasic disposition of Abraxane was similar for both a 3—hr and 30-min infusion.
`There was a linear PK between 135 and 375 mg/m2 (Figure 7). CL and V2 decrease
`slightly with increasing dose, and the resulting half-life remains constant across different
`dose levels. At the dose of 375 mg/rnz, CL and VZ decrease significantly, which makes
`Abraxane half-life much shorter than the values at other dose levels.
`
`Dose (m glm 2)
`
`5OD<
`
`L :
`
`3u:
`r:
`
`Figure 7 Total Paclitaxel AUCm across Different groups
`
`In summary, there is a linear PK of Abraxane between 80-375 mg/rn2 (Figure 8) after
`pooling data from all four clinical studies.
`a
`
`15
`
`
`
`

`

`R2 = 0.4973
`
`(a)O8C)
`
`
`
`AUClhr‘nglml)
`
`
`
`Dose (mglmZ)
`
`Study COOS-0
`
`the patients in the two treatment arms (Abraxane or Taxol) had no
`In this study,
`statistically significant differences with respect to age, weight, BSA or height.
`
`The plot of the mean total paclitaxel concentration vs. time is presented in Figure 9. A
`summary of the estimated PK parameters for paclitaxel administered as both Abraxane
`and Taxol is listed in Table 5.
`
`Faditad Waumme'fine
`
` Figure 8 Total Paclitaxel AUCm vs. Dose (Data from four clinical studies)
`
`mm
`
`mm
`
`murmurs!“mu 3
`
`4: EE
`
`a
`
`0
`
`1D
`
`3)
`
`H)
`4D
`as
`TlmStmaaldl'finmflbJ‘s)
`
`69
`
`H)
`
`m
`
`Figure 9 Plot of Mean Total Paclitaxel Concentration versus Time with Standard
`Error Bars for both Abraxane and Taxol
`
`16
`
`

`

`
`
`Table 5 Summary of Paclitaxel PK Parameters for Abraxane and Taxol
`
`ABE-007
`
`Parameter
`
`Mean
`
`(‘l thlir' mi
`
`3]
`
`l3.
`
`\ leh Ill. :JI‘E
`
`,. (it?
`
`3‘I-a3*u
`
`t
`
`w
`
`.3}
`
`‘30
`
`I:
`_‘
`
`-JI
`..
`
`"R"
`
`L?‘t 2
`13.-
`
`E-lfm
`
`3118
`
`l
`
`
`
`.I...»a
`
`.J'
`
`p—va Inc
`
`I 01) 18
`("MEI
`
`{1.018
`
`{I . 5 24
`
`0.031%
`
`~' QUUE
`
`, GIN“
`
`7:. 0110}
`' 0A 37?
`
`8.3?“
`
`0.983
`
`
`
` A:
`
`.3! ($111"
`
`1 173.36
`
`=1 'Ji line-hr ml. 1r
`
`
`
`2
`
`\1 ( lsll'iluu‘
`can meld!
`mar—hr mi. 1
`( min.
`
`
`
`
`
`329113 (1
`
`I
`mg ml
`('Hiuula
`c. :1 metal
`
`I
`III§_'EI1|
`lmmlltu
`
`L:
`
`2.65
`
`2?.6
`
`r :l.r" .
`
`n 5m
`
`llgllirl
`
`_‘S I"
`
`L.»
`
`X
`
`in»
`
`17.1
`
`ill}
`
`{1033 - mm
`{U533
`
`”1.5
`2‘)_h
`Ll?
`
`205
`
`if}
`
`28
`
`[3.0
`
`Ht)
`
`ill:
`
`for Abraxane 260 mg/m2 and Taxol 175 rug/m2 are not
`The paclitaxel AUCmr
`significantly different. The terminal elimination rate constants (11) are nearly identical.
`Compared to Taxol, Abraxane showed higher total clearance (43%) and larger volume of
`distribution (53%).
`
`How does the PK of the drug and its major active metabolites in healthy volunteers
`compare to that in patients?
`
`The PK of Abraxane has not been studied in healthy adults,
`between the PK in healthy volunteers and patients is not known.
`
`therefore comparison
`
`17
`
`
`
`

`

`C.
`
`Intrinsic Factors
`
`What intrinsic factors influence exposure (PK usually) and/or response and what is the
`impact of any differences in exposure on eflicucy or safety responses?
`
`Cl. Influence on Drug Exposure
`
`The applicant reported that age had no effect on paclitaxel PK parameters.
`
`In Study DM97—123, five out of sixteen patients were aged 65 years or older. None of
`these patients had abnormal hepatic or renal function. The PK parameters of the elderly
`patient populations are listed in Table 6.
`
`Table 6 PK Parameters of Abraxane in Elderly Patient Populations in Study DM97—
`123
`
`Number 6.: Dose
`
`(Uhn'mz)
`
`(hr)
`
`or me
`
`Pharmacoklnetic Parameters
`
`Patient
`Cm“
`AUC
`CL
`ti};
`
`(ngfml)
`_
`(hrt'ng/ml)
`
`
`Patient Type
`
`65 years and
`older
`
`
`
`II!
`
`t l
`
`sum —
`7
`I
`,
`Patient #3: 3—hour iiifusron
`
`0
`
`The PK parameters from the elderly patients were similar to those of young patients.
`
`C2. Influence on Age and Race on Efficacy Responses
`
`Of the 233 patients in a Phase 3 pivotal study (Study CA012-0) using the recommended
`dose and schedule of Abraxane, 14% were older than 65 years. Efficacy appeared similar
`in elderly and younger patients (Table 7). No toxicities occurred notably more frequently
`among elderly patients who received Abraxane. No overall differences in safety or
`effectiveness were observed between these patients and younger patients.
`
`Most of the patients (96.6%) were Caucasian. Data was too sparse for a meaningful
`exploratory Subgroup analysis by race.
`
`
`
`18
`
`

`

`Table 7 Subgroup Analysis by Age: Exploratory Results of FDA-Confirmed
`recTLRR (All Randomized Patients)
`
`(w
`
`
`
`Abraxane
`
`[N 2 233]
`
`No. of FDA-Confirmed Responders
`Response Rate
`(95% Binomial Confidence Interval)
`
`CA'gezfi‘Si"
`,.
`.
`.
`‘
`U
`W
`
`20.4%
`
`(14.83% — 25.97%)
`
`p
`’
`‘
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`No. of FDA-Confirmed Responders —
`Response Rate
`28.1%
`
`95% Binomial Confidence Interval
`15.55% — 43.70%
`
`
`
`
`
`D. Extrinsic Factors
`
`Were anyformal drug interaction studies performed and are they necessary?
`
`Because of the same active entity (paclitaxel) of Abraxane (260 mg/mz) and Taxol (260
`mg/mz), the information obtained from Taxol drug—drug interaction can be applied to
`Abraxane. No formal CYP—based drug-drug interaction studies are necessary.
`
`In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was
`metabolized primarily to 60t—hydr0xypaclitaxel by the cytochrome P450 (CYP) isozyme
`CYPZCS;
`and to two minor metabolites,
`3’—p—hydroxypaclitaxel and 60L,
`3’—p—
`dihydroxypaclitaxel, by CYP3A4. The PK of paclitaxel may be altered in-vivo as a result
`of interactions with compounds that are substrates. In Study DM97—123, two out of
`sixteen patients had Quinine and Ritalin, which are metabolized by the CYP enzymes
`involving paclitaxel metabolism. The PK parameters of these special populations are
`listed in Table 8.
`
`Co—administration of Quinine and Ritalin did not change the PK of paclitaxel. However,
`the result was obtained from only 1 patient each.
`
`19
`
`

`

`Table 8 PK Parameters of Patients with co-administration of Quinine and Ritalin in
`Study DM97—123
`
`Pharmacokinctic Parameters
`
`
`Patient
`
`
`c...
`AUC
`CL
` Patient Type
`Number & Dose
`
`
`
`(lir‘nglml)
`(ngiml)
`
`Concomitant
`
`
`medications Quininc
`
`
`9
`
`Ritalin
`
`
` .4 ' A ..' u I: 1r“ .2 nun '31.,
`
`
`(Uhrlm’)
`
`E. General Biopharmaceutics
`
`Were the different Abraxane batches/formulations used in the Clinical Studies?
`
`investigational
`the different Abraxane clinical
`in the Abraxane PK studies,
`Yes.
`formulations were used (Table 9). Product codes used in the PK clinical trials are listed in
`Table 10. Abraxane with product code 103450, which was used in the comparative PK
`study (CAOOS—O), is the formulation that will be marketed.
`
`There are no formal bioequivalence studies conducted to compare these formulations. In
`order to compare them, PK data were pooled from clinical studies CAOOS—O, CAOIZ-O
`and CAOOS-O. The mean dose—corrected AUCoo for these formulations versus product
`codes is shown in Figure 10. There is no apparent difference among these formulations.
`
`Comparison of Different Formulation (mean, SD)
`
`50 ll
`40
`
`30
`
`AUCITotalDose
`
`101150
`
`103350
`Product Code
`
`103450
`
`Figure 10 Dose Corrected AUCm vs. Product Codes
`
`20
`
`
`
`

`

`Table 9 Comparison of Abraxane Clinical Investigational Formulations “
`
`,
`
`if
`!
`i
`I
`
`3
`
`_
`
`101150
`30
`
`-
`
`3
`
`.
`
`Product (Iodc
`103350
`mo
`
`5
`
`»
`
`I
`1
`
`i
`
`
`
`.
`
`103450
`~ “‘
`100
`
`4
`
`
`
`[ (‘umponcot
`1‘
`fr
`‘
`‘
`a
`E mmam [ang'fifl ml. Vial)
`-_-"""
`{ liumun :‘xibumiu {lllgfi‘3g‘l111v1'éil} A
`_ _‘
`5
`PI
`{ ('unccmmuouul‘ Rcmnstmuccl Ruspcmim‘.
`g
`(mg l’oclituxcl mil}
`Mmmwkk fl“;
`____
`1 pH ot‘Rccomtllulcd Mmpcnsioo
`“is lnrmulnlion of imlwidual batches ofdcvclopmcnl lol-a {in 1mm ul'puchluxcl um! human albuzmn comcnn Much “on: no: umgnul formal product code numbers‘ is:
`can kin! m ihc tux! “main. in 'lahlc K for ouch iul qullI-UUTF.
`I! We cwca-n‘nsmlmn of human ollmmin mu not aadjmlcd prior 1-
`mugs.
`“margin-.1] rum-ml lb bilhml on {he mncculmlmn ol‘humun albumin 1n 1hr linul lmmtllalcd suxpcminn prltll‘ I;
`any I). Thc 11:111le uluc in lhc l‘lslishcd product is approxunalcly ‘JUB my, Hui
`gun,
`
`.
`
`L.
`
`,——-
`
`i'ormulation. tllcrvfurc thc concentration may vary Within the “mod
`
`h.—
`a
`
`n
`
`
`
`
`
`
`
`
`
`
`Table 10 Product Code Used in Clinical Trials
`
`101150
`
`103450
`
`Product Code
`
`
`
`
`
`
`103350
`
`
`Stud Protocol Number
`
`BMW-123
`DM97-123
`CAOOS-O
`
`
`
`CAOOS-O
`CAOOS-O
`CAOOS-O
`
`
`CA012-0
`
`
`
`

`

`What is the relative bioavailability of the proposed to-be-marketed formulation to the
`pivotal clinical trial?
`
`There is no such information available for Abraxane in the submission. The applicant
`only reported that when the concentration of paclitaxel was within the solubility range
`(paclitaxel concentration of 20ug/mL),
`the release was immediate (Figure 11). The
`release of paclitaxel from Abraxane was influenced by the solubility of paclitaxel and
`was not altered by storage conditions for up to
`..._-
`12th}
`
`(Ell 0 -
`i7
`1
`
`such
`{(30%
`
`«3;! U
`
`
`
`”/3i’m.”meRelea‘mi
`
`,-
`
`Figure 11 Percent of Paclitaxel Released in Phosphate Buffered Saline (pH 7.4),
`Abraxane (Lot # 01020738) at Various Storage Conditions for 9 Months
`
`F. Analytical Section
`
`F].
`
`How are the active moieties identified and measured in the plasma in the
`clinical pharmacology and biopharmaceatics studies?
`
`For initial studies of Abraxane, plasma samples were assayed using a validated, sensitive,
`specific, high performance liquid chromatographic mass spectrometry (HPLC—MS)
`method. Subsequently,
`~-----
`_
`.---
`method was developed for assay of Abraxane for
`
`the PKhstudies.
`
`F2.
`
`Which metabolites have been selectedfor analysis and why?
`
`The concentrations of total paclitaxel and its two metabolites, 6(1-hydroxypaclitaxel
`(primary metabolite) and 3’—p-hydroxypaclitaxel, were measured in whole blood, plasma,
`urine and feces to assess the elimination pathway of Abraxane.
`
`22
`
`
`
`

`

`F3.
`
`For all moieties measured, is five, bound or total measured? What is the basis
`for that decision, ifany, and is it appropriate?
`
`For all moieties, the total form is measured.
`
`is the bioanalytical method that is used to assess concentrations of
`F4. What
`Abraxane?
`
`and Taxol. Several Liquid
`ingredient of Abraxane
`active
`the
`is
`Paclitaxel
`Chromatography Mass Spectrometric methods, with Deuterated d5- paclitaxel as internal
`standard (IS), were developed by
`"I
`The concentrations of total
`paclitaxel and its two metabolites, 60t—hydroxypaclitaxel and 3’—p—hydroxypaclitaxel were
`measured in whole blood, plasma, urine and feces. The different assays are listed in Table
`ll. These assays were validated with the intra—day and inter-day accuracy and precision
`within i15% and are acceptable.
`
`Table 11 Analytical Methods used in Abraxane PK Studies
`
`Assay
`
`CAOOS— 0.2mL HPLC-
`0
`lasma
`
`‘fll’
`
`.
`
`.___)
`
`Paclitaxel
`
`DM97—
`123
`
`CAOIZ— whole
`0
`blood
`
`feces
`
`-
`
`.
`
`_
`
`'-
`
`-
`
`Paclitaxel
`
`paclitaxel and
`two metabolites,
`60t-
`
`hydroxypaclitaxel
`and 3’-p—
`h drox paclitaxel
`
`
`
`0
`
`lood
`
`.. _a__
`
`Reference
`
`llakan Gullu, Ergun Topal, Nurzen Sezgin,
`Irfan Barutcu, Alpay Turan Sezgin,
`1.
`Ramazan Ozdemir Effect of Paclitaxel Administration on Electrocardiographic
`Parameters Reflecting Ventricular
`lletcrogem'ty. The Medical Journal of Kocatepe
`2003;1: 42—46
`
`23
`
`
`
`

`

` '3' 5/ Page(s) Withheld
`
`§ 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`__/_ § 552(b)(5) Draft Labeling
`
`
`
`

`

`Appendices B: Individual Study Review
`
`1. Study CA005—0
`
`A Phase I Trial of ABI—007 Administered Weekly for Three Doses Every 4 Weeks In
`Patients with Advanc