Bioequivalence of Two Tiotropium Dry Powder Inhalers and the Utility of Realistic Impactor Testing.

Introduction: Inhaled antimuscarinics are a cornerstone of the management of chronic obstructive pulmonary disease. This article details a series of five pharmacokinetic (PK) studies comparing a generic tiotropium dry powder inhaler (DPI) to Spiriva HandiHaler, the realistic in vitro methods used to support those studies, and the related in vitro-in vivo correlations (IVIVCs). Methods: All five PK studies were of open-label, single-dose, crossover design with test and reference treatments administered to healthy subjects. Following unexpected results in the first three PK studies, a realistic impactor method was developed comprising an Oropharyngeal Consortium (OPC) mouth-throat and simulated inspiratory profiles in conjunction with a Next Generation Impactor (NGI). Mass fractions and the in vitro whole lung dose were estimated for the test product and Spiriva^® HandiHaler^® using this method, and IVIVCs derived. Results: Bioequivalence could not be demonstrated for C_max in the first three PK studies (test/reference ratios ranging from 83.1% to 131.8%), although was observed for AUC_t. Reanalysis of the corresponding biobatches with the realistic NGI method revealed in vitro ratios aligned with these PK data (in contrast to the compendial NGI data) and thus inadvertent selection of "mismatched" biobatches. Two further PK studies were undertaken, supported by the realistic NGI method. With the comparison of test and reference products similarly positioned within their respective product performance distributions, bioequivalence was confirmed in both studies. IVIVCs based on mass fractions as per the realistic NGI method were robust and highly predictive of PK outcomes. Conclusions: The test tiotropium DPI and Spiriva HandiHaler were bioequivalent when equitable biobatch comparisons, based on realistic NGI testing, were performed. The observations from this program support the utility of realistic test methods for inhaled product development.