The Effects of Clarithromycin on the Pharmacokinetics of Apixaban in Healthy Volunteers: A Single-Sequence Crossover Study.

ABSTRACT

BACKGROUND: This was an open-label, phase I, nonrandomized, single-sequence, crossover study to evaluate the effect of concomitant administration of multiple doses of clarithromycin on the single-dose exposure, safety, and tolerability of apixaban in healthy subjects. METHODS: In total, 19 subjects received a single oral dose of apixaban 10 mg on day 1. On day 4, subjects began receiving oral clarithromycin immediate release (IR) 500 mg twice daily (bid) for 4 days. On day 8, subjects received oral apixaban 10 mg and oral clarithromycin IR 500 mg bid. Oral clarithromycin IR 500 mg bid was given alone on days 9 and 10. RESULTS: Compared with apixaban alone, coadministration of apixaban with clarithromycin resulted in increased apixaban exposure. The adjusted geometric mean ratio (GMR) was 1.299 (90% confidence interval [CI] 1.220-1.384) for peak plasma concentration (Cmax), whereas the adjusted GMR for the area under the concentration curve (AUC(INF)) was 1.595 (90% CI 1.506-1.698). The mean half-life and median time to Cmax of apixaban were comparable with and without concomitant administration of clarithromycin. Administration of apixaban and clarithromycin concomitantly did not result in increased adverse events compared with administration of either agent alone. All adverse events were mild in intensity. CONCLUSIONS: Apixaban Cmax and AUC(INF) increased 30% and 60%, respectively, when multiple doses of clarithromycin were coadministered with apixaban versus administration of apixaban alone. The increase in apixaban Cmax and AUC(INF) with concomitant clarithromycin was less than that which has been observed when apixaban was given with ketoconazole. Administration of apixaban alone and in combination with clarithromycin bid was safe and generally well-tolerated by the healthy adult subjects in this study. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifier number NCT02912234.