Effect of rifampicin and clarithromycin on the CYP3A activity in patients with Mycobacterium avium complex

Abstract

The prevalence of pulmonary infections caused by nontuberculous mycobacteria (NTM) is increasing worldwide. Furthermore, the treatment of infections caused by the Mycobacterium avium-intracellulare complex (MAC) remains challenging. The cytochrome P450 (CYP) enzyme inducer, rifampicin, and the CYP inhibitor, clarithromycin, have clinical activity against MAC and key drugs in the treatment of MAC infection. The interaction of rifampicin and clarithromycin may influence the therapeutic process. Thirty-one Japanese chemo-naïve patients with pulmonary MAC infection were included in the study. Before and after 7-day administration of rifampicin and clarithromycin, the pharmacokinetics of midazolam, a CYP3A-specific probe, were analyzed. The concentrations of midazolam were determined by liquid chromatography-tandem mass spectrometry. None of the patients were receiving any other medications that might affect CYP3A activity. Of the patients, 24 (77.4%) were infected with Mycobacterium avium (M. avium) and 7 (22.6%) were infected with Mycobacterium intracellulare (M. intracellulare). The concentrations of midazolam were significantly reduced with administration of rifampicin and clarithromycin [the median (range) was 1.75 (0.70-8.22) to 1.04 (0.30-2.63) ng/mL, P<0.0001]. The differences in midazolam levels were not correlated with clinical characteristics. Coadministration of rifampicin and clarithromycin may increase CYP3A enzymatic activity.