Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.

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Nassr N, Huennemeyer A, Herzog R, von Richter O, Hermann R, Koch M, Duffy K, Zech K, Lahu G

Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.

Br J Clin Pharmacol. 2009 Oct;68(4):580-7. doi: 10.1111/j.1365-2125.2009.03478.x.

PubMed ID

19843061 [ View in PubMed

]

Abstract

AIMS: To evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of roflumilast and roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity. METHODS: Sixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of roflumilast 500 microg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5-15. Plasma concentrations of roflumilast and roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and C(max) of roflumilast and roflumilast N-oxide and for oral apparent clearance (CL/F) of roflumilast were estimated. RESULTS: During the steady-state of rifampicin, the AUC(0-infinity) of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); C(max) by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC(0-infinity) decreased by 56% (0.44; CI 0.36, 0.55); C(max) increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48). CONCLUSIONS: Co-administration of rifampicin and roflumilast led to a reduction in total PDE4 inhibitory activity of roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of roflumilast.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Rifampicin	Cytochrome P450 1A2	Protein	Humans	Unknown	Inducer	Details

Drug Interactions

Drugs	Interaction
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