Comparison of Pharmacokinetic and Pharmacodynamic Effects of Two Hydrofluoroalkane Formulations of Salmeterol

Abstract

Introduction: To compare the Pharmacokinetic (PK) and Pharmacodynamic (PD) effects of two Hydrofluoroalkane (HFA) formulations of salmeterol xinafoate (Test HFA formulation, Cipla Ltd., India; Reference HFA formulation, Allen and Hanburys, UK) administered using pressurized metered dose inhalers. Methods: Three separate randomized, crossover, PK studies and one PD study comparing the efficacy and safety of the two HFA formulations of salmeterol xinafoate (25 μg per actuation) in healthy subjects were conducted. The PK assessments of the two formulations were done without charcoal blockade, with charcoal blockade, and with a Volumatic spacer device using a single dose. A PD study was also conducted to evaluate the systemic exposure of the two formulations using three different doses (50 μg, 150 μg and 300 μg). Results: In the PK study without charcoal, the 90% CI for the difference between the two formulations for AUC0-t was within the bioequivalence limits of 80-125%; however, Cmax marginally exceeded the upper bioequivalence limit to 136%. In the PK study with charcoal, the 90% CI for the difference between the two formulations for Cmax was within the bioequivalence limits of 80-125%; however, AUC0-t marginally exceeded the upper bioequivalence limit to 128%. The impact of marginally higher systemic exposure was therefore further evaluated in the PD study. The PD study confirmed there were no greater systemic safety effects of the test formulation on the primary PD endpoints such as heart rate and serum potassium as well as on other safety PD endpoints such as blood glucose and QTc interval. The PK study with spacer demonstrated bioequivalence between the test and reference formulations. Both formulations were safe and well tolerated. Conclusion: The test HFA formulation of salmeterol was therapeutically equivalent to the reference HFA formulation of salmeterol when used with and without a spacer.