ABSTRACT
OBJECTIVE: To investigate whether a pharmacokinetic drug-drug interaction exists between theophylline (THEO), a CYP1A2 substrate with a narrow therapeutic index, and the concomitant substrate roflumilast (ROF), a novel selective PDE4 inhibitor partially metabolized by CYP1A2. MATERIALS AND METHODS: In an open-label, 2-period, crossover study, Treatment A (oral ROF 500 µg q.d. on Days 6 - 10 in addition to oral THEO 375 mg b.i.d. on Days 1 - 10) and treatment B (oral ROF 500 µg q.d. on Days 1 - 5) were administered consecutively in random order to each of 24 healthy adult subjects. Both periods were separated by a wash-out phase of at least 10 days. Plasma samples for pharmacokinetic evaluation (AUC, Cmax, t1/2, tmax) including percent peak-trough fluctuation (%PTF) of THEO were taken. Point estimates and the 90% confidence interval of the geometric mean ratios were calculated for AUC and Cmax and descriptive statistics for other pharmacokinetic parameters. RESULTS: Concomitant administration of ROF did not alter pharmacokinetics of THEO. With coadministered THEO, only steady-state total exposure to ROF (AUC) was increased by 28% whereas other pharmacokinetic parameters (t1/2, Cmax, tmax) of ROF and of the active metabolite roflumilast-N-oxide (R-NO), its main contributor to the pharmacodynamic effects, remained unchanged. CONCLUSIONS: Neither ROF nor its main metabolite had any impact on the metabolism of the concomitant CYP1A2 substrate THEO in humans. Though co-administration of THEO resulted in a minor increase (28%) in total ROF exposure, no safety or tolerability concerns and no altered total PDE4 inhibition of both ROF and R-NO, were observed.
Subject(s)
Aminopyridines/pharmacokinetics , Benzamides/pharmacokinetics , Bronchodilator Agents/pharmacokinetics , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Theophylline/pharmacokinetics , Adolescent , Adult , Area Under Curve , Blood Pressure/drug effects , Body Temperature/drug effects , Bronchodilator Agents/adverse effects , Cross-Over Studies , Cyclopropanes/pharmacokinetics , Cytochrome P-450 CYP1A2/metabolism , Drug Interactions , Female , Half-Life , Heart Rate/drug effects , Humans , Male , Middle Aged , Quality Control , Theophylline/adverse effects , Therapeutic Equivalency , Young AdultABSTRACT
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.
