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, C_max, t_1/2, t_max) 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 C_max 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 (t_1/2, C_max, t_max) 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.

Author Details

Authors

• G. Böhmer¹
• C.H. Gleiter¹
• A. Hünnemeyer²
• G. Lahu²
• T.D. Bethke²

Departments

• ¹ Department of Clinical Pharmacology, University of Tübingen, Tübingen, and
• ² Nycomed GmbH, Konstanz, Germany

Address

Dr. T.D. Bethke
Nycomed Deutschland GmbH
Moltkestrasse 4
78467 Konstanz, Germany
Email: [email protected]

Citation