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 CL(CR) < 30 ml/ min/1.73 m²; otherwise healthy) and matched (sex, age, weight, and height) healthy control subjects (n = 12; CL(CR) > 80 ml/min/1.73 m²) were enrolled into an open-label, parallelgroup study. Single dose (500 μg, 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-∞)), maximum plasma concentration (C(max))) and a small increase in elimination half-life (t(1/2)) of roflumilast (-1%; -6%; +19%, respectively) and roflumilast N-oxide (-%; 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.