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 developed for COPD
treatment. Roflumilast N-oxide is the major metabolite with similar
mechanism of action. The exposure difference between different races
have been observed, but the need for dose adjustment have been
controversial. The present study compared the pharmacokinetics of a
single dose of the original oral roflumilast tablets (Daliresp®) 0.5 mg
in healthy Chinese and Caucasian subjects under uniform conditions. The
Chinese subjects were found to have longer t1/2, higher AUC0-t, AUCinf
and Cmax than the Caucasian subjects. Compared to Caucasian subjects,
the point estimate on geometric mean of AUC0-t and AUCinf in Chinese
subjects was respectively 22% and 25% higher for roflumilast, and 46%
and 48% higher for roflumilast N-oxide. The point estimate on geometric
mean of Cmax 9% higher for roflumilast, and 24% higher for its
N-oxide. After body weight normalization, the difference of
pharmacokinetics (PK) exposure reduced but did not eliminate. Compared
to the Caucasians, tPDE4i in Chinese subjects was 44% higher. After
body- weight normalization, the difference reduced to 27%. Safety
analysis showed signs indicating Chinese were less tolerant to
roflumilast than Caucasians, or have different pharmacodynamic response.
Our study suggests a dose of roflumilast lower than 0.5 mg daily for
Chinese patients or future clinical trials. More dose exploration
studies are needed to determine the optimal doses of roflumilast for
Chinese COPD patients.