Clarithromycin substantially increases steady-state bosentan exposure in healthy volunteers.

ABSTRACT: AIMS:The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination. METHODS:We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Sixteen healthy volunteers received therapeutic doses of bosentan (125?mg twice daily) for 14 days and clarithromycin (500?mg twice daily) concomitantly for the last 4 days, and bosentan pharmacokinetics was assessed on days 1, 10 and 14. RESULTS:Clarithromycin significantly increased bosentan area under the plasma concentration-time curve of the dosing interval 3.7-fold and peak concentration 3.8-fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance. CONCLUSIONS:Clarithromycin substantially increases the exposure to bosentan, suggesting that dose reductions may be necessary.

SUBMITTER: Markert C 

PROVIDER: S-EPMC3895355 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature