CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202834Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) CLINICAL PHARMACOLOGY REVIEW NDA: 202834 Brand Name: FycompaTM Generic Name: Perampanel Dosage Form & Strength: Immediate Release Tablet (2, 4, 6, 8, 10 and 12 mg) Indication: Adjunctive therapy for partial-onset seizures in patients aged 12 years and above Applicant: Eisai Co. Submission: 505(b)(1), Standard Submission Dates: 12/22/2011, 07/13/2012, 08/10/2012, 08/21/2012, 09/05/2012, 09/10/2012, 09/17/2012 OND Division: OND-1/Division of Neurology Drug Products OCP Divisions: OCP/Division of Clinical Pharmacology-1 (DCP-1) Primary Reviewer: Xinning Yang, Ph.D. Secondary Reviewer: Ta-Chen Wu, Ph.D. Team Leader: Angela Yuxin Men, M.D., Ph.D. Ta-Chen Wu, Ph.D. (Acting) Pharmacometrics Reviewer: Joo-Yeon Lee, Ph.D. Pharmacometrics Team Leader: Atul Bhattaram, Ph.D. (Acting) The OCP office level briefing was held on September 20, 2012. Table of Contents 4. APPENDICES......................................................................................................... 4 4.4 INDIVIDUAL STUDY REVIEW.................................................................................. 4 4.4.1 IN VITRO STUDIES ................................................................................................................. 4 Study B00033: Protein Binding of E2007 in Rat, Dog and Human Plasma.......................................... 4 Study AE-4737-G: Protein Binding of 14C-E2007 to Human Serum Protein (in vitro) ...................... 4 Study B06013: Blood to Plasma Concentration Ratio of 14C-E2007 in Rat, Dog, Monkey and Human .................................................................................................................................... 5 Study B04006: Estimation of human CYP Isoforms Responsible for E2007 Metabolism.................... 6 Study B06012: Assessment of E2007 Metabolism by Recombinant Human CYP3A5 ........................ 7 Study B05007: Structural Analysis of E2007 Metabolites Produced by Human Liver Microsomes .... 8 Study B07001: Effect of Ketoconazole and CYP3A4 Antibody on the Formation of E2007 Metabolites in Human Liver Microsomes ............................................................................. 10 Study B00030: Kinetic and Inhibition Studies Using Human Liver Microsomes with E2007 ........... 12 Study AE-4739-G: Inhibitory Study of E2007 for CYP Isoforms Using Human Liver Microsomes . 13 Study XT095036: In Vitro Evaluation of E2007 as a Direct Inhibitor of UGT Enzymes in Human Liver Microsomes.............................................................................................................. 16 Study GE-0045: Enzyme Induction Study of E2007 in Primary Cultured Human Hepatocytes......... 17 Study XT093050: In Vitro Evaluation of E2007 as an Inducer of Cytochrome P450 (CYP) and UDP- glucuronosyltransferase (UGT) Expression in Cultured Human Hepatocytes .................. 20 Study GE-0258-G: Cellular Transport Study of E2007 Using MDRl Expressing Cell....................... 24 Study DMPKT2011-002: Transport of E2007 across Human Breast Cancer Resistance Protein (BCRP) -Expressed Cell Monolayer and the Inhibition Potency of E2007 on BCRP....... 29 Study GE-0404-G: Transport Study of E2007 Using OATP1B1 and OATP1B3 Expressing Oocytes... ……………………………………………………………………………………………...…...30 Study B06015: Characterization of E2007 Transport via Human Organic Anion and Organic Cation Transporters...................................................................................................................... 32 1 Reference ID: 3206870 4.4.2. IN VIVO STUDIES...................................................................................................................... 39 Study E2007-E044-001: Ascending single dose safety and tolerability study of E2007 in healthy male volunteers............................................................................................................................... 39 Study E2007-E044-002: A double-blind, randomized study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple oral doses of E2007 as compared to placebo in healthy adult male subjects ........................................................................................................ 44 Study E2007-E044-003: A randomised, open label, single dose, 2-way crossover, food effect study of E2007 in healthy male and female volunteers............................................................................ 50 Study E2007-E044-004: A randomised, double-blind, single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of E2007 in elderly subjects................................ 55 Study E2007-E044-005: An open label, 2-way crossover study to evaluate the interaction between E2007 and ketoconazole................................................................................................................. 58 Study E2007-E044-006: An open label E2007 and carbamazepine interaction study in healthy male voluteers …………………………………………………………………………………….…...61 Study E2007-E044-007: A Single Radio-labelled Dose Absorption, Metabolism and Elimination Study of 14C-E2007 in Healthy Elderly Volunteers ...................................................................... 67 Study E2007-A001-008: An Open-Label, Randomized, Single Oral Dose Bioequivalence Assessment of Two Formulations of E2007 in Healthy Subjects ...................................................................... 74 Study E2007-E044-009: A two part, randomized study to identify an E2007 dosing regimen suitable to achieve supratherapeutic plasma concentrations in healthy young volunteers........................... 77 Study E2007-J081-010: Phase I Ascending Single Dose Study of E2007 in Healthy Japanese Male volunteers ………………………………………………………………………………….……...86 Study E2007-A001-013: A Randomized, Double-blind, Active- and Placebo-controlled, Combined Fixed-sequence, Parallel Group Study to Investigate the Effect of E2007 on the QT Interval Duration in Healthy Volunteers..................................................................................................... 91 Study E2007-A001-014: An open label, fixed sequence, crossover study to investigate the pharmacokinetic interaction between E2007 and midazolam........................................................ 94 Study E2007-E044-015: An open-label, parallel group study to explore the pharmacokinetics of E2007 in subjects with reduced hepatic function .......................................................................... 98 Study E2007-E044-016: A randomized, open label, crossover study to demonstrate dose strength equivalence between 2 mg and 4 mg E2007 tablet strengths in healthy young volunteers ......... 102 Study E2007-E044-017: An Open-label, Single-center Study to Determine the Absolute Oral Bioavailability and to Investigate the Metabolite Profile of Perampanel Following Administration of an Intravenous Microdose of 14C-Perampanel Solution and a Single Oral Dose of Perampanel in Healthy Male Subjects............................................................................................................. 104 Study E2007-E044-019: An open label, three treatment, fixed sequence crossover study to investigate the effect of E2007 on the combined ethinylestradiol and levonorgestrel oral contraceptive pill (Microgynon® 30 ED) in healthy pre-menopausal female volunteers........................................ 115 Study E2007-A001-023: A Double-blind Ascending Single-Dose Safety and Tolerability Study to Find the Maximum Tolerated Dose of E2007 in Healthy Recreational Polydrug Users ............ 118 Study E2007-A001-024: A Randomized, Double-Blind, Placebo- and Active-Controlled Crossover Study to Evaluate the Abuse Potential of Perampanel (E2007) in Healthy Recreational Polydrug Users…………………………………………………………………………………………….122 Study E2007-E044-025: An open-label, three treatment, fixed sequence study to investigate the pharmacokinetic interaction between E2007 and levodopa in healthy volunteers ...................... 128 Study E2007-J081-026: Phase I Ascending Repeated-Dose Study of E2007 in Japanese Healthy Adult Male Volunteers ............................................................................................................... 131 Study E2007-E044-028: A Randomized, Open-label, Crossover Study to Compare Relative Bioavailability Between a (b) (4) and a 4 mg Tablet of Perampanel in Healthy Subjects .................................................................................................. 138 Study E2007-E044-029: An Open-label Study to Investigate the Potential Pharmacokinetic Interaction of Perampanel with Oral Contraceptives in Healthy Female Subjects ...................... 140 Study E2007-E044-037: A Randomized, Open-label, Crossover Study to Demonstrate Bioequivalence Between 6 × 2-mg Tablets of Perampanel and a Single 12-mg Tablet of Perampanel in Healthy Subjects .................................................................................................. 147 Study E2007-A001-039: Study E2007-A001-039: A Randomized, Open-label, Crossover Study to 2 Reference ID: 3206870 Demonstrate Bioequivalence Between 3 × 2-mg Tablets of Perampanel and a Single 6-mg Tablet of Perampanel in Healthy Subjects ............................................................................................ 150 Study E2007-A001-040: A Randomized, Open-label, Crossover