Influence Of Renal Impairment On The Pharmacokinetics Of Oral Roflumilast: An Open-Label, Parallel-Group, Single-Center Study

Objective: Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved in the European Union for the treatment of severe COPD. Roflumilast and its metabolites are mainly (70% of total radioactivity) eliminated via the kidneys as glucuronides. The potential impact of renal impairment on the pharmacokinetics of roflumilast and its active main metabolite roflumilast N-oxide were characterized. Materials and methods: Patients (n = 12) with severe renal impairment (creatinine clearance CLCR < 30 ml/min/1.73 m(2); otherwise healthy) and matched (sex, age, weight, and height) healthy control subjects (n = 12; CLCR > 80 ml/min/1.73 m(2)) were enrolled into an open-label, parallel-group study. Single dose (500 mu g, p.o.) pharmacokinetics and safety/tolerability of roflumilast and roflumilast N-oxide were compared between both groups. Results: A minor decrease of exposure (area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)), maximum plasma concentration (C-max)) and a small increase in elimination half-life (t(1/2)) of roflumilast (-21%; -16%; +19%, respectively) and roflumilast N-oxide (-7%; ND; +30%, respectively) were observed in renally impaired patients compared with healthy subjects. No relevant differences in safety and tolerability were observed between groups. Conclusions: The pharmacokinetic changes observed in patients with renal impairment are of small magnitude without clinical importance. A dose adjustment or a change in the administration interval of roflumilast is not necessary in patients with renal impairment.