Lack of pharmacokinetic interactions between cilomilast and theophylline or smoking in healthy volunteers

The pharmacokinetic profile of cilomilast (Ariflo((R))), 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 mug.h/mL and 7.70 +/- 2.25 mug.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.