What is already known about this subject
Cytochrome P450 (CYP) 3A4 plays a prominent role in the metabolism of many drugs, which in turn implies, that changes in the activity of this enzyme caused by, for example, co-administered drugs, might result in clinically significant drug interactions.Roflumilast, a targeted PDE4 inhibitor in clinical development for the treatment of COPD and asthma, is partly metabolized by CYP3A4, and thus may have the potential to inhibit its activity.
What this study adds
The results of this study show that therapeutic steady-state concentrations of roflumilast and its active metabolite roflumilast N-oxide do not alter the disposition of the CYP3A substrate midazolam.Therefore, roflumilast treatment has a low susceptibility to alter the clearance of drugs metabolized by CYP3A4.
The aim of this study was to investigate the effects of roflumilast, an investigational PDE4 inhibitor for the treatment of COPD and asthma, on the pharmacokinetics of the CYP3A probe drug midazolam and its major metabolites.
In an open, randomized (for midazolam treatment sequence) study, 18 healthy male subjects received single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart) alone, repeated doses of roflumilast (500 µg once daily for 14 days) alone, and repeated doses of roflumilast together with single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart).
A comparison of clearance and peak and systemic exposure to midazolam following administration of roflumilast indicated no effect of roflumilast dosed to steady state on the pharmacokinetics of midazolam. Point estimates (90% CI) were 0.97 (0.84, 1.13) for the AUC of i.v. midazolam and 0.98 (0.82, 1.17) for that of oral midazolam with and without roflumilast.
Therapeutic steady state concentrations of roflumilast and its N-oxide do not alter the disposition of the CYP3A substrate midazolam in healthy subjects. This finding suggests that roflumilast is unlikely to alter the clearance of drugs that are metabolized by CYP3A4.