CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202324Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) RECOMMENDATION: 1. The proposed film coat weight gain (b) (4) 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 The Applicant proposed a film coat weight (b) (4) to control the weight of film coating applied to tablets. 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 (b) (4) % of film coat has any impact on dissolution with supporting data, if available. Sponsor Response (b) (4) 4 Page(s) has been Withheld in Full as B4 (CCI/ TS) immediately following this 2 Reference ID: 3076627 --------------------------------------------------------------------------------------------------------- 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 NDA 202324 Submission Date: April 14, 2011 Brand Name: Inlyta® Generic Name: Axitinib Formulation: 1 mg and 5 mg tablets OCP Reviewer: Sarah Schrieber, PharmD OCP Team Leader: Qi Liu, PhD Pharmacometrics Reviewer: Nitin Mehrotra, PhD Pharmacometrics Team Leader: Christine Garnett, PharmD Pharmacogenomics Reviewer: Rosane Charlab Orbach, PhD Pharmacogenomics Team Leader: Issam Zineh, PharmD OCP Division: Division of Clinical Pharmacology V ORM Division: Division of Drug Oncology Products Sponsor: Pfizer Submission Type; Code: NME/0000/1 Dosing regimen: Axitinib 5 mg orally twice daily without regards to food. Indication: Axitinib in patients with advanced renal cell carcinoma (RCC). 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 NDA 202324 Review – Axitinib Reference ID: 3072768 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 (b) (4) 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 NDA 202324 Review – Axitinib Reference ID: 3072768 2 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