Clinical Pharmacology Biopharmaceutics Review(S)
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CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 206500Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) OFFICE OF CLINICAL PHARMACOLOGY REVIEW NDA 206-500 Submission Date 09/05/2014 Brand Name To-be-determined Generic Name Rolapitant hydrochloride DCP Reviewer Insook Kim, Ph.D. DCP Team Leader Sue-Chih Lee, Ph.D. PM Reviewer Jee Eun Lee, Ph.D. PM Team Leader Nitin Mehrotra, Ph.D. Genomics Reviewer Sarah Dorff, Ph.D. Genomics Team Leader Christian Grimstein, Ph.D. OCP Division Division of Clinical Pharmacology 3 OND Division Division of Gastroenterology and Inborn Errors Products Sponsor Tesaro, Inc. Relevant IND(s) IND 72,754 Submission Type; Code Original Submission New Molecular Entity Formulation; Strengths; 90 mg rolapitant (equivalent to 100 mg rolapitant Regimen hydrochloride) tablet Oral administration of 180 mg rolapitant at 1-2 hours prior to the start of chemotherapy. Once per chemotherapy cycle Proposed Indication In combination with other antiemetic agents in adults for the prevention of (b) (4) delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy including, but not limited to, highly emetogenic chemotherapy Table of Contents 1 Executive Summary .................................................................................................... 2 1.1 Recommendations ................................................................................................. 2 1.2 Post-Marketing Commitments .............................................................................. 2 1.3 Summary of Clinical Pharmacology and Biopharmaceutics Findings ................. 3 2 Question-Based Review .............................................................................................. 6 2.1 General Attributes of the drug .............................................................................. 6 2.2 General Clinical Pharmacology ............................................................................ 8 2.5 General Biopharmaceutics .................................................................................. 54 2.6 Analytical Section ............................................................................................... 57 3 Detailed Labeling Recommendations ....................................................................... 60 4 Appendices ................................................................................................................ 61 Reference ID: 3748397 4.1 Pharmacometric Review ..................................................................................... 61 4.2 OCP Filing Form ................................................................................................ 68 1 Executive Summary Rolapitant is a substance P/neurokinin 1 (NK1) -receptor antagonist and is proposed for use by the sponsor for the prevention of (b) (4) delayed nausea and vomiting associated with emetogenic cancer chemotherapy (CINV). The proposed dosage regimen is a single-dose administration of 180 mg rolapitant at 1-2 hour prior to the initiation of chemotherapy cycle in combination with a 5-HT3 receptor antagonist and a corticosteroid. 1.1 Recommendations The Office of Clinical Pharmacology has reviewed the submission and found acceptable from a clinical pharmacology standpoint provided mutual agreement on the labeling languages is reached. 1.2 Post-Marketing Commitments a. Recommended study: In vivo drug interaction study with a sensitive substrate of CYP2D6 to study the duration of CYP2D6 inhibition beyond 7 days after a single dose administration of rolapitant Rationale: Rolapitant is a moderate CYP2D6 inhibitor with inhibitory effects observed on 7 days after a single dose administration. The target patient population is cancer patients who will receive emetogenic chemotherapeutics and is likely to be on multiple other medications. Especially rolapitant will be administered every 2-4 weeks depending on the number of and the interval between chemotherapy cycles over a course of therapy. This PMC will be used to inform how long the inhibition of CYP2D6 enzyme lasts after a single dose administration of rolapitant as so to properly inform the labeling and to mitigate the potential risk with increased systemic exposure of concomitant CYP2D6 substrates. b. Recommended study: In vitro study to evaluate an inhibitory potential of rolapitant on OATP1B1 and OATP1B3 Rationale: Inhibition of hepatic transporters, OATP1B1 and OATP1B3 can cause an increase in systemic exposure of OATP1B1 or OATP1B3 substrates such as statin. The inhibitory potential of rolapitant on OATP1B1 and OATP1B3 was not evaluated to assess drug interaction potential. c. Recommended study: In vitro studies to evaluate an inhibitory potential of rolapitant on renal transporters i.e. organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) transporters organic anion transporter 1 (OAT1), and organic anion transporter 3 (OAT3) Rationale: Inhibition of renal transporters may lead to an increase in systemic exposure to concomitant drugs that are substrates of these transporters, which include but not limited to, metformin and cisplatin (OCT2 and MATEs), and methotrexate (OAT1, OAT3). The inhibitory 2 Reference ID: 3748397 potential of rolapitant on kidney transporters (OCT2, MATE1, MATE-2K, OAT1, and OAT3) was not evaluated to assess drug interaction potential. 1.3 Summary of Clinical Pharmacology and Biopharmaceutics Findings The clinical efficacy and safety of rolapitant was studied in combination with a standard of care i.e. a 5-HT3 antagonist and a corticosteroid and compared with placebo treatment which was also given with a standard of care. The efficacy was evaluated based on the proportion of patients who had complete response (CR) i.e. no emesis, and no rescue medication over 120 hours in delayed (25-120 h), acute (0-24 h) and overall (0-120 h) phases. Dose-Response Relationship Efficacy The proposed dose of 180 mg rolapitant was supported by a Phase 2 dose-finding study and three Phase 3 clinical trials where the efficacy and safety of rolapitant was evaluated with 180 mg dose. (b) (4) In a Phase 2 trial in patients who received cisplatin- based chemotherapy, there was a dose-dependent increase in the CR rate in the dose range from 9 mg to 180 mg rolapitant. Only 180 mg dose but not lower doses showed, significantly higher CR rates in delayed, overall, and acute phases compared to placebo treatment. In addition, within doses ranging from 4.5 mg to 180 mg, there was a dose-dependent increase in the NK1 receptor occupancy in the brain at 120 hours after single-dose administration of rolapitant. The proportion of patients with CR was significantly higher than that in placebo group in the delayed and overall phases in two phase 3 trials for highly emetogenic chemotherapy (P04832, P04833) and one phase 3 trial for moderately emetogenic chemotherapy (P04834). On the other hand, a statistically significant increase in CR rate in the acute phase was shown only in P04832 but not in Studies P04833 and P04834. For more details, see the Biostatistics Review. Safety Across clinical trials, nausea, anorexia, vomiting, fatigue, neutropenia and headache were the most frequently reported treatment-emergent adverse events (TEAE). No apparent dose-dependent increase in the incident of treatment-emergent adverse events was noted in the dose range from 9 mg to 180 mg in patients receiving cisplatin-based chemotherapy (n=90-91 per dose). While doses higher than 180 mg were not studied in cancer patients, no serious adverse events were reported at 720 mg dose in healthy subjects (n=41) 1 and TEAEs were mostly mild in severity except one subject experienced moderate disorientation at 720 mg rolapitant. See the Clinical Review by Dr. Johnson for thorough review of safety. Effects on the QT interval No significant effects on the QTc interval were observed after single dose administration of 720 mg rolapitant in a thorough QT study. 1 Study P0478:Through QT study 3 Reference ID: 3748397 Table 1 the Point Estimates and the 90% CIs Corresponding to the Largest Upper Bounds for Rolapitant and the Largest Lower Bound for Moxifloxacin2) Treatment Time (h) ∆∆QTcF (ms) 90% CI (ms) Rolapitant 180 mg 1 1.3 (-1.5, 4.0) Rolapitant 720 mg 0 1.7 (-1.0, 4.4) Moxifloxacin 400 mg 1 10.4 (7.7, 13.2) Pharmacokinetic/Biopharmaceutics Properties Pharmacokinetics The PK of rolapitant and the effects of rolapitant on other drugs were mainly studied after single- dose administration of rolapitant consistent with the proposed dosage regimen. In efficacy trials, rolapitant was administered once every 2-4 weeks with a median interval of 21 days depending on the chemotherapy regimen. The dosing interval of less 2 weeks was not studied in cancer patients. The pharmacokinetics of rolapitant is characterized by a large apparent volume of distribution with plasma concentrations measurable at a month after a single-dose administration. Upon oral administration, the peak plasma concentration of rolapitant is achieved around 4 hours. Once absorbed, rolapitant is slowly eliminated from the circulation with mean elimination half-life of about 7 days. The systemic exposure (AUC0-120) over 120 hours, during which the efficacy of rolapitant was evaluated, is about 40% of total systemic exposure (AUC0-inf). In cancer patients the apparent total clearance (CL/F) and volume of distribution (Vd/F) is estimated to be 0.96 L/h and 387 L, respectively by a population PK analysis. Rolapitant