BV100 (rifabutin IV) drug interaction studies in healthy subjects with index CYP450 3A probes midazolam and itraconazole.

BACKGROUND

BV100 is a novel intravenous (IV) formulation of rifabutin under development for the treatment of serious Acinetobacter baumannii infections. The primary objectives of these studies were to assess potential pharmacokinetic interactions between BV100 and two index cytochrome P450 3A enzymes (CYP3A) probes, midazolam (substrate) and itraconazole (inhibitor), and to evaluate BV100's safety profile.

METHODS

Two open-label Phase 1 studies were conducted in healthy participants. Study 1 evaluated the impact of multiple IV doses of BV100 (300 mg) on the pharmacokinetics of a single oral dose of midazolam (5 mg). Study 2 assessed the impact of repeated oral doses of itraconazole (200 mg) on the pharmacokinetics of a single IV dose of BV100 (300 mg). Pharmacokinetic parameters [maximum plasma concentration (Cmax), area under the plasma concentration-time curve from zero to 24 hours (AUC0-24), area under the plasma concentration-time curve from zero to infinity (AUC0-∞)] were analysed using geometric means and 90% confidence intervals (CI). Drug-drug interactions (DDIs) were defined as a 90% CI outside the equivalence range of 80%-125%.

RESULTS

Both studies demonstrated DDIs. BV100 increased midazolam metabolism, with Cmax and AUC test/reference ratios of 77% and 53%, respectively. The decreased midazolam AUC (47%) indicated BV100 is a mild/weak CYP3A inducer by EMA/FDA criteria. Itraconazole decreased BV100 metabolism, resulting in increased BV100 exposure (Cmax 1.1-fold; AUC 1.3-1.7-fold), consistent with mild inhibition. BV100 was considered generally safe and well tolerated in both studies, with no serious adverse events reported.

CONCLUSION

BV100 is a mild/weak CYP3A enzyme inducer and a mild substrate for CYP3A inhibitors. However, co-administration with strong CYP3A inhibitors resulted in a disproportionate increase in exposure to the active metabolite 25-O-desacetyl rifabutin, leading to an ∼2-fold increase in total active-moiety exposure. Clinical monitoring is advised when BV100 is co-administered with a strong CYP3A inhibitor. BV100 was safe and well tolerated.