Pulmonary Penetration of Intravenous Rifabutin in Healthy Participants: A Multiple-Dose Pharmacokinetic Study

Carbapenem-resistant Acinetobacter baumannii causes severe respiratory infections with limited therapeutic options and high mortality. Although rifabutin exhibits potent activity against A. baumannii, oral administration results in low bioavailability and variable exposure. An intravenous formulation (BV100) was developed to overcome these limitations. However, human data on pulmonary distribution following intravenous administration are lacking.

In this single-center, open-label study, 36 healthy male participants received intravenous rifabutin 300 mg every 12 hours for 4 days. On Day 4, plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of rifabutin and its active metabolite 25-O-deacetyl-rifabutin were quantified at predefined time-points. Plasma pharmacokinetic parameters were calculated by non-compartmental analysis. Steady-state penetration ratios were calculated as the ELF/AM to plasma AUC ratio over one dosing interval (total AUC_SS,tau).

Rifabutin and 25-O-deacetyl-rifabutin concentrations in ELF and AM exceeded plasma concentrations at all time points. At Day 4, mean C_max was 1.20 and 0.022 mg/L in plasma, 61.1 and 1.18 mg/L in ELF, and 358 and 8.03 mg/L in AM, respectively. Median penetration ratios were 34.5 (25.3-55.3) and 44.2 (18.3-101.1) for ELF, and 310.5 (227.3-497.1) and 430.7 (178.4-984.3) for AM, for rifabutin and 25-O-deacetyl-rifabutin, respectively. Repeated dosing was well tolerated; infusion-site reactions were mitigated by use of peripherally inserted central catheters.

Intravenous rifabutin achieves pulmonary exposures substantially exceeding plasma concentrations, providing a strong pharmacological rationale for further clinical evaluation of BV100 in severe CRAB pneumonia.