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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Rifampicin is an antibiotic that is used to treat pulmonary tuberculosis. It induces several cytochrome P450 (CYP) enzymes and some drug transporter proteins; its greatest effect is as an inducer of CYP3A4 in the liver and in the small intestine.• Mechanistic drug-drug interaction studies with prototypic CYP3A4 inducers provide essential information for clinical drug development of new chemical entities that are metabolized by the involved CYP450 enzymes.• Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor being developed for the treatment of chronic obstructive pulmonary disease.• The pharmacological effect is based on the total PDE4 inhibitory activity, which represents the combined PDE4 inhibitory activity of roflumilast and its major active metabolite, roflumilast N-oxide.• In patients with chronic obstructive pulmonary disease, pulmonary tuberculosis can be an accompanying disease. Thus, the drug-drug interaction between rifampicin and roflumilast is of clinical relevance. WHAT THIS STUDY ADDS• The pharmacokinetics of roflumilast and of its major pharmacologically active metabolite roflumilast N-oxide is affected by co-administration of rifampicin.• The potent induction of CYP3A4 and other CYP450 enzymes (such as CYP2C19 and extrahepatic CYP1A1) by rifampicin has led to a 58% decrease in the total PDE4 inhibitory activity of roflumilast.• Co-administration of rifampicin with roflumilast may reduce the therapeutic efficacy of roflumilast. AIMSTo 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. METHODSSixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of roflumilast 500 mg 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 Cmax of roflumilast and roflumilast N-oxide and for oral apparent clearance (CL/F) of roflumilast were estimated. RESULTSDuring the steady-state of rifampicin, the AUC0 CONCLUSIONSCo-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.

Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

“…In an open-label, randomized, two-period cross-over study involving 12 healthy, fasted, white adult subjects, the absorption of roflumilast (2 × 250 µg immediate release tablets) was rapid and complete after oral administration, with the time to achieve peak plasma concentration (T max ) of approximately 1 hr (55). Roflumilast given orally is highly bioavailable (F = 0.79), bound extensively (98.9%) to plasma proteins, achieves steady-state levels within 4 days of once-daily dosing, has an elimination half-life (t 1/2 ) of 7-25 hr (mean ∼17 hr), and is subject to negligible first pass hepatic metabolism (38,(54)(55)(56)(57). Furthermore, after a single intravenous dose (120 µg) of roflumilast to healthy adult subjects, the CL and volume of distribution (V d ) were 13 L/hr and 2.92 L/kg, respectively, indicating pronounced distribution in tissues (58).…”

“…The pharmacokinetics of roflumilast N-oxide generally are distinct from the parent compound. Thus, the T max is between 4 hr and 12 hr and the maximum observed plasma concentration (C max ) is typically one-to two-fold higher (54,57,(59)(60)(61). Steady-state plasma levels of roflumilast N-oxide are usually achieved within 6 days of once-daily oral administration and the elimination t 1/2 is approximately 27 hr, which is significantly prolonged relative to the parent compound.…”

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

“…The present clinical study was designed to evaluate the pharmacokinetics and metabolism of BRV when coadministered with rifampin, a potent pan-inducer of hepatic and intestinal P450 isoforms (CYP3A4, 2B6, 2C8, 2C9, and 2C19), with numerous clinically relevant interactions reported (Branch et al, 2000;Niemi et al, 2003;Nassr et al, 2009;Tapaninen et al, 2010). The present clinical interaction study also aimed to determine whether rifampin might affect the major metabolic pathway of BRV, namely, its hydrolysis into BRV-AC.…”

The use of roflumilast in COPD: a review

“…As previously mentioned, the N-oxide metabolite accounts for approximately 90% of the PDE4 activity and provides reasonable PDE4 inhibition over 24 hours, allowing for once daily oral administration [13]. There are few clinically important drug interactions apart from potential concerns about the coadministration of roflumilast and rifampicin [14]. The administration of rifampicin, an inducer of cytochrome P450, was shown to cause a reduction in total PDE4 inhibitory activity of about 60%.…”