Pharmacokinetic Bioequivalence of Two Fluticasone Propionate/Salmeterol Dry Powder Inhalers, OT329 Solis, and Advair Diskus

Abstract

SESSION TITLE: COPD: Advances in Pharmacotherapy SESSION TYPE: Original Investigation Slide PRESENTED ON: Tuesday, October 31, 2017 at 11:00 AM - 12:15 PM PURPOSE: OT329 Solis® 100/50 (Oriel Therapeutics, Morrisville, NC, USA) was developed as a fully substitutable generic to Advair Diskus® 100/50 (GSK, Research Triangle Park, NC, USA). Both are multi-dose dry powder oral inhalation products containing 100 mcg fluticasone propionate (FP) and 50 mcg salmeterol for the prophylactic treatment of asthma. The purpose of the current work was to assess the pharmacokinetic (PK) bioequivalence (BE) of these two products. METHODS: Demonstration of PK BE to Advair Diskus 100/50 is impacted by batch-to-batch PK variability [Clin Pharm Therap 2016 100(3):223-231]; use of multiple batches, as is required for in vitro BE testing, provides a BE conclusion that is not highly dependent on the specific batches selected (by chance or intent) and avoids inflated type I and type II error rates [Clin Pharm Therap 2017 101(3):331-340; RDD Europe 2017 Book 1:25-34]. Two approaches were employed in the PK BE assessment of OT329 Solis 100/50 to directly address between-batch variability. First, five individual studies, each with PK comparison of OT329 Solis 100/50 (Test) to Advair Diskus 100/50 (Reference) as the primary endpoint, were analyzed collectively by meta-analysis. This analysis involved comparative PK data from 146 evaluable subjects (156 enrolled) across nine (Test) or eight (Reference) batches (one to three batches per product in each contributing study). The meta-analysis was retrospective because the strong dependence of individual study outcome on batch selection was not known when the studies were initiated. Second, a prospective multiple-batch pivotal PK BE assessment was conducted in 96 subjects (95 evaluable) across 16 batches per product to confirm the outcome of the retrospective meta-analysis. For all studies, a single inhalation was administered to healthy adult subjects in a randomized crossover design. PK blood samples collected predose and to 32-56 hours after inhalation were quantitated by a validated LC/MS-MS method (1-200 pg/mL range). Early PK sampling was frequent (once per minute) to ensure accurate capture of peak plasma levels. Treatment difference estimates were obtained for each study by analysis of variance of log-transformed PK metrics. RESULTS: Bioequivalence was defined per FDA convention as 90% confidence intervals on FP and salmeterol Cmax, AUCt and AUCinf geometric mean Test/Reference ratios within the 0.8000 - 1.2500 BE goalposts. The five-study meta-analysis met the BE requirement on all PK metrics. Subsequently, the prospective multiple-batch pivotal study confirmed the passing PK BE result, also on all PK metrics. Cmax was observed 6-17 minutes (FP) or 3-5 minutes (salmeterol) after inhalation. Within-subject residual error estimates (%CV) were relatively constant across all six studies, with ranges of 21-29% (FP Cmax), 17-21% (FP AUCt and AUCinf), 18-28% (salmeterol Cmax) and 18-22% (salmeterol AUCt and AUCinf). Reference-scaling was not used in the BE analyses. CONCLUSIONS: OT329 Solis 100/50 demonstrates PK BE to Advair Diskus 100/50 in a robust assessment adequately powered to address batch-to-batch variability. CLINICAL IMPLICATIONS: OT329 Solis is intended to ease the healthcare burden in the US by providing a generic option for the control and treatment of asthma. DISCLOSURE: Elise Burmeister Getz: Employee: salary Kevin Carroll: Consultant fee, speaker bureau, advisory committee, etc.: consultant fee The Presenter will be discussing information about an assessment of clinical pharmacokinetic bioequivalence between an FDA-approved product marketed in the US, Advair Diskus 100/50, and a generic candidate, OT329 Solis 100/50. These data have been submitted to the FDA as part of an abbreviated new drug application (ANDA) for OT329 Solis 100/50. The FDA has not yet approved the OT329 Solis 100/50 application.