title: Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults.
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.
  
  
  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.
authors: Department of Clinical Pharmacology, University of Tübingen, Tübingen, Konstanz, Germany.
authors: G
authors: G
authors: Böhmer
authors: C H
authors: CH
authors: Gleiter
authors: A
authors: A
authors: Hünnemeyer
authors: G
authors: G
authors: Lahu
authors: T D
authors: TD
authors: Bethke
mesh_terms: D000293:Adolescent; D000328:Adult; D000631:Aminopyridines / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001549:Benzamides / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003521:Cyclopropanes / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors / Q000493:pharmacokinetics*; D011786:Quality Control; D013806:Theophylline / Q000009:adverse effects / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D001993:Bronchodilator Agents; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2