A Single‐center, Open‐label, Parallel Control Study Comparing the Pharmacokinetics and Safety of a Single Oral Dose of Roflumilast and Its Active Metabolite Roflumilast N‐oxide in Healthy Chinese and Caucasian Volunteers

Abstract

Roflumilast is a phosphodiesterase‐4 inhibitor which treats chronic obstructive pulmonary disease (COPD). Roflumilast N‐oxide is the major metabolite of roflumilast with a similar mechanism of action to roflumilast. Although racial differences in roflumilast drug disposition have been observed, the necessity of dose adjustment is subject to debate. This study compares the pharmacokinetics of a single 500 μg dose of roflumilast in healthy Chinese and Caucasian subjects under uniform conditions. Chinese subjects were found to have longer t1/2 and higher AUC0‐t and Cmax than Caucasian subjects. The point estimates on the geometric mean of AUC0‐t in Chinese subjects were 22% higher for roflumilast and 46% higher for roflumilast N‐oxide. Point estimates on the geometric mean of Cmax were 9% and 24% higher for roflumilast and roflumilast N‐oxide, respectively. Total phosphodiesterase‐4 (PDE4) inhibitory (tPDE4i) activity, a theoretical parameter that describes the combined contribution to PDE4 inhibitory activity of roflumilast and roflumilast N‐oxide, was 44% higher in Chinese subjects than in Caucasian subjects. With about a 10‐fold higher plasma AUC compared to the parent roflumilast and a much longer observed half‐life, roflumilast N‐oxide has been estimated to contribute about 90% of tPDE4i, with 10% attributed to the parent compound roflumilast. Following body weight normalization, these figures were lower but remained significant. Safety analysis showed signs of reduced tolerance or different pharmacodynamic response to roflumilast in Chinese recipients than in Caucasians. Our results suggest that Chinese patients should receive a dose of roflumilast lower than 500 μg daily during future clinical trials.