Single-ascending and multiple-ascending dose study of the pharmacokinetics, safety, and tolerability of BV100 (rifabutin for infusion) in healthy volunteers

BV100 (rifabutin for infusion) is being developed as an intravenous formulation for treating serious or life-threatening infections due to carbapenem-resistant <i>Acinetobacter baumannii</i> in patients with limited treatment options. Phase 1 studies were conducted to characterize the pharmacokinetics (PK), safety, and tolerability of BV100 in healthy volunteers after single and multiple doses. Single-ascending and multiple-ascending dose studies were conducted in healthy subjects to establish the PK profile of BV100. Blood samples were assayed to determine plasma concentrations of rifabutin and the major metabolite 25-O-desacetyl-rifabutin and to determine PK parameters. Subjects were assessed for safety and tolerability. The PK profile of BV100 was generally dose-proportional in the single-ascending dose studies with a <i>t</i>_1/2 of 7.9-56.1 h, and <i>T</i>_max of 1.0-1.75 h and increasing exposure with dose. A q12h versus q24h dosing interval resulted in approximately a 1.5-fold to 2-fold greater exposure of rifabutin. The 25-O-desacetyl-rifabutin metabolite represented <5% of rifabutin activity. Adverse events were more common at higher doses with q24h versus q12h dosing, and with a 60 min infusion time. The most common adverse events were infusion site events, with systemic treatment-emergent adverse events as expected for the known safety profile of rifabutin. No other treatment-related safety issues were identified. BV100 demonstrated a dose-proportional PK profile and was generally safe and well tolerated. Based on these results, BV100 doses of 200-300 mg q12h are undergoing evaluation in a Phase 2 study for treating carbapenem-resistant <i>A. baumannii</i> infections.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04636983 and NCT05087069.