CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202324Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`Application No.-
`
`Submission Dates:
`
`BIOPHARMACEUTICS REVIEW ADDENDUM
`
`Office of New Dru_s Qualitv Assessment
`NDA 202-324
`
`4/13/2011. 12/21/2012. 1/20/2012
`
`Reviewer: Kareen Riviere. Ph.D.
`
`Division of Oncology Products
`
`Secondary Signature: Sandra Suarez Sharp.
`Ph.D.
`
`Biopharmaceutics Lead: Angelica Dorantes.
`Ph.D.
`Date
`
`(”(4) will not likely affect the clinical performance of the drug product.
`
`Sponsor:
`
`Pfizer
`
`Trade Name:
`
`INLYTA®
`
`Generic Name:
`
`Axitinib
`
`Ass' ; ned:
`Date of
`Review:
`
`4/13/201 1
`
`1/25/2012
`
`Indication:
`
`Treatment of advanced renal cell
`carcinoma (RCC)
`
`Type 01' Submission: Original New Drug
`Application
`
`Formulation/strengths:
`
`Immediate Release (IR) Film-Coated
`Tablet/l m- and 5 m
`
`Route of
`Administration:
`
`SUMMARY:
`
`This addendum incorporates the agreements in terms of pending issues not resolved at the time the original
`Biopharmaceutics review was entered into DARRTS on December 12. 2011 by this reviewer.
`
`During the review cycle. the review team had concerns with the coating weight gain because there was no data (i.e..
`dissolution data) supporting the proposed specifications. The Applicant proposed a coating weight gain of (b) (4). The
`ONDQA review team connnunicated to the Applicant that the dissolution data do not support a film coating
`specification
`(5) (4) and recommended to adopt an upper limit for coating weight based on the provided
`dissolution data. In later communications. the Applicant provided dissolution data that support
`(5X4) coating
`weight gain for the 5 mg strength. Although the dissolution data provided do not directly support
`the same
`specification for the 1 mg strength. the review team considers that coating weight gain
`“(4) is acceptable for
`both strengths based on the following information:
`
`In vivo data showing that both strengths are bioequivalent: and
`1.
`2. Formulation characteristics and in vitro dissolution performance of the drug product.
`
`(5)“)
`Additionally. the review team had concerns that the proposed
`design space would provide adequate dissolution of axitinib and communicated this to the
`Applicant during the review cycle. The Applicant responded that
`(b) (4)
`
`(5) (4)
`However. the ONDQA review team later on commtmicated to the Applicant that their proposed design space
`was not acceptable and advised the Applicant to establish target values for the process parameters to
`ensure the formation of axitinib
`(war The Applicant revised their design space: however. there was a concern
`about the
`(”(4). as allowed by the specification. could have. Therefore. the
`Applicant was requested to provide data/justification that undetected
`0’ (4) drug substance polymorphs will not
`affect the bioavailability of the drug product. On a teleconference dated January 19. 2012. the Biopharmaceutics
`review team communicated to the Applicant that based on the information provided on December 21. 2011 and on an
`internal analysis of the exposure-response data for the drug product. the FDA considers that the presence of drug
`substance polymorphs
`
`Reference ID: 3076627
`
`

`

`
`RECOMMENDATION:
`
`
`1. The proposed film coat weight gain
` is acceptable for the 1 mg and 5 mg tablet.
`• This specification is supported by the information received on December 21, 2011 and on the
`bioequivalency between both strengths, the formulation characteristics, and the in vitro dissolution
`performance.
`
`
` Kareen Riviere, PhD Sandra Suarez Sharp, PhD
` Biopharmaceutics Reviewer Senior Biopharmaceutics Reviewer
` Office of New Drugs Quality Assessment Office of New Drugs Quality Assessment
`
` cc: Angelica Dorantes, Ph.D.
`
`Drug Product Film Coating Weight
`
` to control the weight of film coating applied to tablets.
`The Applicant proposed a film coat weight
`However, there no data was submitted supporting this proposed film coat specification.
`
`The following Biopharmaceutics comment related to film coating specification was made in the Information
`Request Letter dated September 26, 2011.
`
`
`FDA Query 36
`Indicate if
`available.
`
`Sponsor Response
`
` % of film coat has any impact on dissolution with supporting data, if
`
`
`
`
`
`
`
`Reference ID: 3076627
`
`2
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`4 Page(s) has been Withheld in Full as B4 (CCI/
`TS) immediately following this
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KAREEN RIVIERE
`01/25/2012
`
`SANDRA SUAREZ
`01/25/2012
`
`Reference ID: 3076627
`
`

`

`
`
`Clinical Pharmacology Review
`202324
`April 14, 2011
`Inlyta®
`Axitinib
`1 mg and 5 mg tablets
`Sarah Schrieber, PharmD
`Qi Liu, PhD
`Nitin Mehrotra, PhD
`Christine Garnett, PharmD
`Rosane Charlab Orbach, PhD
`Issam Zineh, PharmD
`Division of Clinical Pharmacology V
`Division of Drug Oncology Products
`Pfizer
`NME/0000/1
`Axitinib 5 mg orally twice daily without regards to
`food.
`Axitinib in patients with advanced renal cell
`carcinoma (RCC).
`
`
`
`NDA
`Submission Date:
`Brand Name:
`Generic Name:
`Formulation:
`OCP Reviewer:
`OCP Team Leader:
`Pharmacometrics Reviewer:
`Pharmacometrics Team Leader:
`Pharmacogenomics Reviewer:
`Pharmacogenomics Team Leader:
`OCP Division:
`
`ORM Division:
`Sponsor:
`Submission Type; Code:
`Dosing regimen:
`
`Indication:
`
`
`
`
`OCP Briefing was held on December 12, 2011.
`
`Table of Contents
`1 Executive Summary .........................................................................................................................4
`1.1
`Recommendations ...............................................................................................................5
`1.3
`Summary of Clinical Pharmacology Findings.....................................................................5
`2 Question Based Review ...................................................................................................................6
`2.1
`General Attributes ...............................................................................................................6
`2.2
`General Clinical Pharmacology...........................................................................................8
`2.3
`Intrinsic Factors.................................................................................................................24
`2.4
`Extrinsic Factors................................................................................................................30
`2.5
`General Biopharmaceutics ................................................................................................40
`2.6
`Analytical Section .............................................................................................................44
`3 Detailed Labeling Recommendations ............................................................................................50
`
`Reference ID: 3072768
`
`NDA 202324 Review – Axitinib
`1
`
`
`
`

`

`4 Appendices.....................................................................................................................................63
`4.1
`PHARMACOMETRICS REVIEW...................................................................................63
`4. 2
`PHARMACOGEMOMICS Review..................................................................................79
`4.3
`NDA Filing and Review Form ..........................................................................................88
`
`
`Index of Tables
`Table 1. Progression free survival (PFS) in patients with advanced RCC (A4061032). ..............................8
`Table 2. Overview of Clinical Pharmacology Related Studies Submitted in NDA......................................9
`Table 3. Summary of Axitinib PK Parameters in Healthy Volunteers and Patients by Study and Treatment
`Group Following a Single 5 mg Oral Dose of Axitinib in the Fed State. ..........................................16
`Table 4. Pharmacokinetic Parameters for Axitinib
` after Administration of
`single doses of 5 mg and multiple doses of 5 mg twice daily under Fed Conditions in Patients with
`Cancer. ...............................................................................................................................................17
`Table 5. Estimated Geometric Means and Ratios with Associated 90% CI for Pharmacokinetic Parameters
`of Axitinib (total and unbound) Comparing Healthy Volunteers with Mild or Moderate Hepatic
`Impairment to Volunteers without Hepatic Impairment in Study A4061036. ...................................28
`Table 6. Geometric mean (CV%) Pharmacokinetic Parameters for Axitinib (total and unbound) after
`Administration of 5 mg in Healthy Volunteers with Mild or Moderate Hepatic Impairment and
`Volunteers without Hepatic Impairment in Study A4061036............................................................29
`Table 7. Geometric mean (CV%) Pharmacokinetic Parameters for Axitinib (unbound) after
`Administration of 5 mg in Healthy Volunteers with Mild or Moderate Hepatic Impairment and
`Volunteers without Hepatic Impairment in Study A4061036............................................................29
`Table 8. Estimated Geometric Means and Ratios with Associated 90% CI for Pharmacokinetic Parameters
`of Axitinib (unbound) Comparing Healthy Volunteers with Mild or Moderate Hepatic Impairment to
`Volunteers without Hepatic Impairment in Study A4061036............................................................29
`Table 9. Ki values (µM) for axitinib inhibition of CYP activities in human liver microsomes (study PDM-
`020). ...................................................................................................................................................32
`Table 10. Effect of increasing Axitinib (AG-013736) concentration on MDR1-MDCK permeability,
`efflux and inhibition...........................................................................................................................33
`Table 11. Digoxin Papp and net secretory flux values across Caco-2 cell monolayers in the presence of
`increasing concentrations of axitinib..................................................................................................34
`Table 12. Effect of increasing axitinib concentration on BCRP-MDCK permeability, efflux and
`inhibition. ...........................................................................................................................................35
`Table 13. Effect of increasing axitinib concentration on OATP efflux. .....................................................35
`Table 14. Geometric mean (95% CI) pharmacokinetic parameters of axitinib with and without multiple
`doses of ketoconazole.........................................................................................................................36
`Table 15. Effect of multiple doses of ketoconazole on the pharmacokinetics of single dose of axitinib in
`Study A40601004. Test = AG-013736 (axitinib) 5 mg + ketoconazole 400 mg qd (N=28); Reference
`= axitinib 5 mg (AUC, N=31; Cmax: N=32). ....................................................................................36
`Table 16. Geometric mean (CV%) pharmacokinetic parameters of axitinib with and without multiple
`doses of rifampin................................................................................................................................37
`
`Reference ID: 3072768
`
`NDA 202324 Review – Axitinib
`2
`
`
`
`(b) (4)
`
`

`

`Table 17. Effect of multiple doses of rifampin (600 mg once daily) on the single-dose pharmacokinetic
`parameters of axitinib. Test = axitinib 5 mg + Rifampin 600 mg QD; Reference = axitinib 5 mg...38
`Table 18. Mean (CV%) every 3 week paclitaxel plasma pharmacokinetic parameters for Cohorts 1-3.
`Data from 2 subjects were excluded due to PK samples not being collected on Cycle 1 Day 1........39
`Table 19. Mean (CV%) weekly paclitaxel plasma pharmacokinetic parameters for Cohort 4. Data from 1
`subject excluded due to PK samples not being collected on Cycle 2 Day 1. .....................................39
`Table 20. Comparison of Plasma Pharmacokinetics of axitinib in the presence and absence of rabeprazole.
`............................................................................................................................................................40
`Table 21. Solubility of Axitinib in Aqueous Media as a Function of pH at 20°C for at least 24 Hours.....41
`Table 22. Solubility of Axitinib in Organic Solvents after Equilibration for at least 24 hours at 20°C. ....41
`Table 23. Composition of Axitinib Film-Coated Immediate Release 1 mg and 5 mg Tablets...................42
`Table 24. Descriptive Summary of Pharmacokinetic Parameters of Axitinib 5 mg Administration under
`Fasting Conditions, after administration with a Standardized Moderate-fat Meal, or a High-fat Meal
`in Study A4061053.............................................................................................................................43
`Table 25. Estimated Geometric Means and Ratios with Associated 90% CI for Pharmacokinetic
`Parameters of Axitinib Comparing Administration of 5 mg under Fasting Conditions Versus
`Administration with Standardized Moderate-fat or High-fat Meals in Study A4061053. .................43
`Table 26. Summary of Bioanalytical Methods Used in Clinical Studies for Pharmacokinetic
`Measurements of Axitinib..................................................................................................................46
`
`
`Index of Figures
`Figure 1. Structural Formula of axitinib. ......................................................................................................7
`Figure 2. Exposure dependent increase in hypertension (left) and proteinuria (right). Reduction of Dose
`from 5 to 3 mg bid will reduce the risk of hypertension and proteinuria...........................................13
`Figure 3. Occurrence of Diarrhea and Fatigue Increases with Axitinib Exposures....................................13
`Figure 4. Dose Titration Based on Tolerability Reduces Variability in Axitinib Exposures......................14
`Figure 5. No effect of healthy vs. patients on the clearance of axitinib......................................................18
`Figure 6. Median Cumulative Percent of Radioactive Dose Recovered in Urine and Feces at Specified
`Intervals after a Single 5 mg (100 µCi) Oral Dose of [14C]-axitinib to Healthy Male Subjects in
`Study A4061003 (N=6)......................................................................................................................20
`Figure 7. Proposed In Vivo Axitinib Metabolic Schema.............................................................................21
`Figure 8. Single dose Log AUCinf (ng*h/mL) vs. Log of Dose (mg) in the Dose Proportionality Studies
`(A4060010, A4061044, and A4061050) in the Dose Range of 2 to 30 mg. ......................................23
`Figure 9. Steady-state Log AUC0-24 (ng*h/mL) vs. Log of the Total Daily Dose (mg) in the Dose
`Proportionality Studies (A4060010 and A4061019) in the Dose Range of 1 to 20 mg Twice Daily.23
`Figure 10. No effect of gender on the clearance of axitinib........................................................................24
`Figure 11. Axitinib clearance in Japanese vs. non-Japanese patients from the popPK model. ..................25
`Figure 12. No effect of weight on the clearance of axitinib........................................................................25
`Figure 13. Axitinib clearance in <60 and >60 year subjects.......................................................................26
`Figure 14. No effect of UGT1A1*28 (left) and CYP2C19 (right) genotype on axitinib clearance............26
`
`Reference ID: 3072768
`
`NDA 202324 Review – Axitinib
`3
`
`
`
`

`

`Figure 15. No effect of CrCL in axitinib clearance (left) and individual observed and median with 25th -
`75th percentile range Axitinib Clearance (L/h) after Administration of 5 mg in Healthy Volunteers
`and/or Patients with Normal (N=381), Mild (N=139), Moderate (N=64), Severe (N=5), or End-stage
`(N=1) Renal Impairment (right).........................................................................................................27
`Figure 16. Individual and Geometric mean with 95% CI Axitinib (total and unbound) AUClast (ng*h/ml)
`after Administration of 5 mg in Healthy Volunteers with Mild or Moderate Hepatic Impairment and
`Volunteers without Hepatic Impairment in Study A4061036............................................................28
`Figure 17. Axitinib clearance in non-smokers, active-smokers and ex-smokers........................................31
`Figure 18. The median time-concentration profiles of axitinib in healthy subjects on a semi-log scale,
`following a single 5 mg oral axitinib dose alone (N=31) or coadministered with 400 mg
`ketoconazole once daily (N=28) in a 2-treatment, 2-period, 2-sequence crossover design. ..............37
`Figure 19. The median time-concentration profiles of axitinib in healthy subjects on a semi-log scale,
`following a single 5 mg oral axitinib dose alone (N=40) or coadministered with 600 mg rifampin
`once daily (N=39) in a 2-treatment, 2-period, 2-sequence crossover design. ....................................38
`
`
`Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor (VEGFR)-1, -2, and -
`3. The current submission is the original NDA for axitinib for the treatment of advanced renal
`cell carcinoma (RCC).
`
`To support the efficacy in advanced renal cell carcinoma, the sponsor conducted one
`randomized, controlled phase 3 trial. Patients in the phase 3 trial were randomized to receive
`axitinib tablets 5 mg twice daily or sorafenib 400 mg twice daily. Progression free survival (PFS)
`was the primary endpoint. The median PFS for the axitinib treatment arm was 6.7 months
`compared to 4.7 months for patients receiving sorafenib.
`
`Exposure-safety analysis demonstrated that there was exposure dependent increase in
`hypertension, proteinuria, fatigue, and diarrhea. The proposed dose reduction strategy (5 to 3 to 2
`mg bid) to manage hypertension and proteinuria is acceptable. Additionally, the dose titration
`scheme, which is the same as that used in the phase 3 trial (5 to 7 to 10 mg based on tolerability),
`is reasonable and can reduce variability in axitinib exposures based on observed pharmacokinetic
`data.
`
`The pharmacokinetics of axitinib has been evaluated in twenty studies in healthy volunteers and
`cancer patients. Following oral administration, the median axitinib plasma Tmax ranges between
`2.5 – 4.1 hours and the mean half-life ranges between 2.5 – 6.1 hours. The mean absolute
`bioavailability of axitinib after an oral 5 mg dose is 58%. A clinically significant effect of food
`was not observed; axitinib may be administered with or without food.
`
`The results of the hepatic impairment study support the labeling recommendations of reducing
`the axitinib dose by half for patients with moderate hepatic impairment. No dose adjustment is
`warranted for patients with mild hepatic impairment. Patients with severe hepatic impairment
`have not been studied. Based on the population pharmacokinetic analysis, no adjustment to the
`starting dose is needed for patients with pre-existing mild, moderate, or severe renal impairment.
`As only one subject was enrolled with end-stage renal impairment, a definitive conclusion
`
`
`
`Executive Summary
`
` 1
`
`Reference ID: 3072768
`
`NDA 202324 Review – Axitinib
`4
`
`
`
`

`

`Recommendations
`
`Phase IV Requirements
`
`regarding the effect of end-stage renal impairment on axitinib exposure cannot be made.
`
`In vitro data indicate that axitinib is primarily metabolized by CYP3A4/5. In drug-drug
`interaction studies, ketoconazole (a strong CYP3A4/5 inhibitor) increased axitinib exposure by
`106%, while rifampin (a strong CYP3A4/5 inducer) decreased axitinib exposure by 80%.
`Therefore, concomitant use of strong inhibitors or inducers of CYP3A4/5 should be avoided.
`However, if a strong CYP3A4/5 inhibitor must be co-administered, the axitinib dose should be
`reduced by half.
`
`1.1
`
`The Office of Clinical Pharmacology Divisions of Clinical Pharmacology 5, Pharmacometrics,
`and Pharmacogenomics have reviewed the information contained in NDA 202324. This NDA is
`considered acceptable from a clinical pharmacology perspective.
`
`Labeling Recommendations
`
`Please refer to Section 3 - Detailed Labeling Recommendations.
`
`1.2
`
`None.
`
`1.3
`
`Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor (VEGFR)-1, -2, and -
`3. Axitinib is being developed for oral use in the treatment of advanced renal cell carcinoma
`(RCC).
`
`The applicant has conducted twenty studies in healthy volunteers, and patients with cancer to
`evaluate the safety and pharmacokinetics of axitinib. The Tmax of axitinib typically occurs 2.5-4.1
`hours following oral administration, and the concentrations of axitinib decreased over time with
`a half-life of approximately 2.5-6.1 hours after a single 5 mg axitinib oral dose in the fed state.
`No major deviation from dose proportionality was observed following multiple dosing in the
`dose range of 1 to 20 mg twice daily. There are no significant differences between the
`pharmacokinetics in healthy volunteers and patients with cancer. A moderate-fat meal decreased
`the AUC of axitinib by 10%, while a high-fat increased the AUC of axitinib by 19%.
`
`After administration of radio-labeled axitinib in healthy subjects, approximately 41% of the
`radioactivity was recovered in feces and approximately 23% was recovered in urine. Unchanged
`axitinib was not detected in urine, but was the major component identified in feces (12% of the
`dose). In plasma, unchanged axitinib accounted for approximately 20% of the circulating
`radioactivity. Two metabolites of axitinib have been detected in human blood and these
`metabolites showed ≥400-times less activity than axitinib itself. A hepatic impairment study in
`subjects with moderate hepatic impairment showed that the average AUC was 2-fold higher that
`found in subjects with normal hepatic function. A dose reduction by 50% for patients with
`
`Summary of Clinical Pharmacology Findings
`
`Reference ID: 3072768
`
`NDA 202324 Review – Axitinib
`5
`
`
`
`

`

`moderate hepatic impairment is recommended.
`
`Axitinib is a substrate of CYP3A4/5, P-glycoprotein, and UGT1A1. Drug-drug interaction
`studies indicate a 106% increase in axitinib exposure (AUC) when administered with
`ketoconazole and an 80% reduction in axitinib AUC when administered with rifampin. Axitinib
`inhibited CYP2C8 (I/Ki=0.15) and 1A2 (I/Ki=0.11) in vitro; however, in vivo, co-administration
`of axitinib did not increase paclitaxel plasma concentrations, indicating a lack of CYP2C8
`inhibition. Axitinib was not found to induce any cytochrome P-450 enzymes in vitro. The
`aqueous solubility of axitinib is pH dependent. Drug-drug interaction studies indicate a 15%
`decrease in axitinib AUC and 42% decrease in axitinib Cmax when administered rabeprazole.
`
`Exposure-safety analysis was conducted by pooling data from three phase 2 and one phase 3
`trial. There was exposure dependent increase in hypertension, proteinuria, fatigue, and diarrhea.
`The proposed dose reduction strategy (5 to 3 to 2 mg bid) to manage hypertension and
`proteinuria is acceptable since these adverse events are exposure related. Additionally, the dose
`titration scheme proposed by the sponsor, which is the same as that used in the phase 3 trial (5 to
`7 to 10 mg based on tolerability), is reasonable and would reduce variability in axitinib
`exposures.
`
`Signatures:
` Team Leader: Qi Liu, PhD
`Reviewer: Sarah J. Schrieber, PharmD
`Division of Clinical Pharmacology 5
`Division of Clinical Pharmacology 5
` Team Leader: Christine Garnett, PharmD
`Reviewer: Nitin Mehrotra, PhD
`Division of Pharmacometrics
`Division of Pharmacometrics
` Team Leader: Issam Zineh, PharmD
`Reviewer: Rosane Charlab-Orbach, PhD
`Division of Pharmacogenomics
`Division of Pharmacogenomics
`Division Director, NAM Atiqur Rahman, PhD
`Division of Clinical Pharmacology 5
`Cc: DDOP: CSO - L Skarupa; MTL - J Johnson; MO - A McKee, Safety MO -
`
`DCP-
`Reviewers - S Schrieber (CP), N Mehrotra (PM) R Charlab-Orbach (GG)
`5:
`CP TL - Q Liu , PM TL - C Garnett GG TL - I Zineh
`DDD - B Booth DD - A Rahman
`
`QUESTION BASED REVIEW
`
`2.1 GENERAL ATTRIBUTES
`
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of the
`drug substance and the formulation of the drug product as they relate to clinical
`pharmacology and biopharmaceutics review?
`
`Axitinib has been developed as 1 mg and 5 mg film-coated tablets for oral administration. The 1
`mg tablet is a red oval shaped tablet debossed with “Pfizer” on one side and “1 XNB” on the
`other. The 5 mg tablet is a red triangular shaped tablet debossed with “Pfizer” on one side and “5
`XNB” on the other.
`
`
` 2
`
`Reference ID: 3072768
`
`NDA 202324 Review – Axitinib
`6
`
`
`
`

`

`Physical-chemical properties
`1. Structural formula:
`
`
`Figure 1. Structural Formula of axitinib.
`
`
`2. Established names: Axitinib, AG-013736
`3. Molecular Weight: 386.5 Daltons
`4. Molecular Formula: C22H18N4OS
`5. Partition coefficient (log P): 3.5
`6. Dissociation Constant (pKa): 4.8
`7. Chemical Name: N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-
`benzamide
`8. Melting Point: 225°C
`9. Solubility: Axitinib solubility in aqueous media decreases with increasing pH. It is
`soluble in excess of 0.2 μg/mL in aqueous media over the range pH 1.1 to pH 7.8. See
`section 2.5.1.
`
`
`2.1.2 What are the proposed mechanisms of action and therapeutic indications?
`
`Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor (VEGFR)-1, -2, and -
`3. These receptors are implicated in pathologic angiogenesis, tumor growth, and metastatic
`progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial
`cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft
`tumor vasculature that expressed the target in vivo and produced tumor growth delay, regression,
`and inhibition of metastases in many experimental models of cancer.
`
`The proposed indication is for axitinib in patients with advanced renal cell carcinoma (RCC).
`
`2.1.3 What are the proposed dosage(s) and route(s) of administration?
`
`The applicant proposes a dosing regimen of 5 mg of oral axitinib administered twice daily
`without regard to food. Patients who tolerate 5 mg twice daily may have the dose increased to 7
`mg bid, and further to a maximum of 10 mg twice daily if they meet the following criteria:
`• No Adverse drug reactions >Grade 2 for two consecutive weeks
`• Normotensive
`• Not receiving anti-hypertension medication
`
`
`
`Reference ID: 3072768
`
`NDA 202324 Review – Axitinib
`7
`
`
`
`

`

`2.2
`
`GENERAL CLINICAL PHARMACOLOGY
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used
`
`to support dosing or claims?
`
`A single pivotal trial in patients with advanced renal cell carcinoma (RCC) was conducted to
`support the efficacy claim.
`
`Pivotal Phase 3 Trial in Patients with advanced RCC (A4061032)
`The pivotal trial was a phase 3 multi-center, 2-arm, randomized, open-label study of axitinib (5
`mg twice daily with food) or sorafenib (400 mg twice daily) in patients with advanced RCC
`whose disease had progressed on or after treatment with one prior systemic first—line therapy,
`including: sunitinib-, bevacizumab-, temsirolimus—, or cytokine-containing regimens. This study
`randomized 723 patients 1:1 to receive axitinib or sorafenib. During the study, the dose of
`axitinib was allowed to be escalated from 5 mg twice daily to 7 mg twice daily and 10 mg twice
`daily based on patient safety and tolerability.
`
`The primary efficacy endpoint was progression free survival (PFS) and Table 1 below shows a
`summary of the sponsors results based on this primary endpoint.
`
`Table 1. Pro ession free survival (PFS) in atients with advanced RCC (A4061032).
`—_-_-I
`Median PFS in Months
`
`W)
`
`W656,
`
`
`
`—m_
`Hazard Ratio 95% C
`CI, confidence interval
`
`< 0-0001
`0.67 0.54, 0.81
`
`The secondary efficacy endpoints were overall response rate (ORR), overall survival (OS), and
`duration of response (DR).
`
`A total of 19 completed studies and l ongoing study were used to support
`Pharmacology and Biophannaceutics Section of the NDA (Table 2).
`
`the Clinical
`
`Healthy subject studies:
`0 Nine Phase 1 studies — Dose proportionality (A4061050), bioavailability. (A4061007),
`relative bioavailability / bioequivalence (A4061021, A4061033, A4061052, A4061063), food
`effect (A4061006, A4061053) and mass balance (A4061003)
`
`0 One organ impairment study - Hepatic (A4061036)
`0 Two drug interaction studies — CYP3A4/5 inhibitor (A4061004), 3A4/5 inducer (A4061026)
`o QT study — substudy of A4061004.
`
`Cancer patient studies:
`
`0 Three Phase 1 studies — Advanced solid tumor; Dose escalation (A4060010, A4060019,
`A406 1 044)
`
`0 Four Phase 2 studies - Advanced RCC (A4061046 [ongoing], A4061012, A4061023,
`A4061035)
`0 One Phase 3 study — Advanced RCC (A4061032)
`
`Reference ID: 3072768
`
`NDA 202324 Review — Axitinib
`8
`
`

`

`
`Clinical Pharmacology Reports of data from more than one study:
`The axitinib plasma concentration data from several studies were used to develop a population
`pharmacokinetic (popPK) model (reports PMAR-00075, PMAR-00079) to investigate the
`potential influence of covariates that contribute significantly to between-patient variability in
`pharmacokinetic parameters of axitinib. The model was also used to characterize the exposure-
`safety relationships for select adverse events (population PK/PD).
`
`Table 2. Overview of Clinical Pharmacology Related Studies Submitted in NDA.
`Study Description/Design
`Study
`Subjects Evaluated
`Treatment Regimen/
`Number
`Sex M/F
`Duration
`Start/End
`Age (yr): Mean (SD)
`Route of Administration
`Date
`Batch Number
`Race
`(W/B/His/As/Other)
`Bioavailability Studies
`Phase 1, randomized, open-label,
`A4061007
`single-dose, 3-treatment, 2-way
`02 Aug 2005/ 19
`crossover study designed to
`Aug 2005
`determine the absolute
`
`bioavailability of axitinib tablets
`vs. IV solution formulation in
`healthy subjects.
`
`Axitinib 5 mg po with a 7-day washout between
`each dosing period. Subjects were randomized to 1
`of 2 treatments sequences (ABC or BAC).
`Treatment Groups:
`A: 1 mg axitinib IV fasted
`B: 5 mg axitinib po fasted
`C: 5 mg axitinib po fed
`Formulation:
`IV administration
`
` solution for
`
`, fed
`
`, fed
`
`
`
` particle size,
`
` particle size,
`
` particle size,
`
`Subjects: 16
`Sex: 14 M / 2 F
`Age (yr): 37.4 (14.9)
`Race (W/B/Ot): 12/3/1
`
`Comparative Bioavailability and Bioequivalence Studies
`Subjects: 40
`Phase 1, open-label, randomized,
`A4061021
`Sex: 38 M / 2 F
`single-dose, 2-sequence, 3-period
`06 Jul 2006/ 15
`Age (yr): 33.4 (13.3)
`crossover trial designed to
`Aug 2006
`Race (W/B/As/Ot): 29/5/3/3
`determine the relative
`
`
`bioavailability of 5 mg
`
`fed healthy subjects.
`
`
`in
`
`A4061033
`02 Jan 2008/ 21
`Feb 2008
`
`
`Phase 1, open-label, single-dose,
`randomized, 4-sequence, 4-period,
`crossover study to determine the
`relative bioavailability of 5 mg
`
`Subjects: 56 M
`Age (yr): 34.6 (10.3)
`Race (W/B/As/Ot): 27/2/25/2
`
`
`
`in fed healthy
`
`male subjects.
`
`A4061052
`13 Jul 2009/ 02
`Sep 2009
`
`A4061053
`01 Jul 2009/ 18
`Jul 2009
`
`
`Phase 1, open-label, randomized,
`single-dose, 2-sequence, 4-period
`crossover to establish the
`bioequivalence of test 5 x1 mg
`axitinib tablet to reference 1 x 5
`mg axitinib tablet in fasted healthy
`male subjects.
`
`Phase 1, open-label, randomized,
`single-dose, 6-sequence, 3-period
`crossover to assess the effect of
`food vs. fasting on Form XLI
`axitinib pharmacokinetics in
`healthy male subjects.
`
`Subjects: 60 M
`Age (yr): 30.6 (7.0)
`Race (As): 60
`
`
`Subjects: 30 M
`Age (yr): 37.2 (9.5)
`Race (W/B): 29/1
`
`
`Axitinib 5 mg was administered under fed
`conditions according to the treatment sequence
`