Lack of pharmacokinetic interactions between cilomilast and theophylline or smoking in healthy volunteers.
The pharmacokinetic profile of cilomilast (Ariflo), a selective phosphodiesterase 4 (PDE4) inhibitor, was investigated in three separate studies. Two of these studies explored the drug interaction potential of cilomilast with the nonselective PDE inhibitor, theophylline, and a third study compared the pharmacokinetic profile of cilomilast in smokers and nonsmokers. Repeated administration of cilomilast had no effect on the steady-state pharmacokinetics of theophylline in either a pilot dose-ranging or definitive therapeutic study. At therapeutic doses, the point estimate and 90% confidence interval for theophylline AUC(0-12) and C(max) were completely contained within the range (0.8, 1.25). Similarly, repeated administration of theophylline had little clinically relevant effect on the steady-state pharmacokinetics of cilomilast when compared to placebo, as only slight average increases in cilomilast AUC(0-12) and C(max) (6% and 3%, respectively) were observed. In addition, mean cilomilast exposure (AUC(0- infinity )) was found to be similar in both smokers and nonsmokers (8.47 +/- 2.20 microg*h/mL and 7.70 +/- 2.25 microg*h/mL, respectively). Throughout all three studies, cilomilast was well tolerated, and concomitant use of these selective and nonselective inhibitors, although unlikely in the clinic, is hypothetically feasible. Taken together, these studies clearly differentiate cilomilast from theophylline for drug-drug liability issues in a smoker and nonsmoker population, as well as highlight the potential to switch from one drug to another without undue clinical concern.
Clinical Pharmacology Unit, GlaxoSmithKline, New Frontiers Science Park, Third Ave, Harlow, UK.
Robert D
RD
Murdoch
Barry
B
Zussman
J Paul
JP
Schofield
Dawn M
DM
Webber
D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D002264:Carboxylic Acids; D018592:Cross-Over Studies; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D012907:Smoking / Q000378:metabolism*; D013806:Theophylline / Q000493:pharmacokinetics*
D001993:Bronchodilator Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; C433247:Cilomilast; D013806:Theophylline