Single-dose intrapulmonary pharmacokinetics of rifapentine in normal subjects

The intrapulmonary pharmacokinetics of rifapentine were studied in 30 volun teers who received a single, oral dose of rifapentine (600 mg). Subgroups o f five subjects each underwent bronchoscopy and bronchoalveolar lavage (BAL ) at timed intervals following drug administration. Drug concentrations, in cluding the concentration of the primary metabolite 25-desacetyl rifapentin e, were determined in plasma, BAL fluid, and alveolar cells (AC) by high-pr essure liquid chromatography. The concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The concentration-time data were fit to two-compartment (plasma) or one-compartment (AC and ELF) models. The peak concentrations in plasma, ELF, and AC, 26.2, 3.7, and 5.3 mu g/ml, respectively, occurred at 5, 5, and 7 h after drug administration, respectively, The half-lives and areas under the curve for plasma, ELF, an d AC were 18.3 h and 520 mu g.h/ml, 20.8 h and 111 mu g.h/ml, and 13.0 h an d 133 mu g.h/ml, respectively, Although the intrapulmonary rifapentine conc entrations were less than the plasma rifapentine concentrations at all time periods, they remained above the proposed breakpoint for M. tuberculosis ( 0.5 mu g/ml) for the 48-h observation period. These data provide a pharmaco kinetic rationale for extended-interval dosing. The optimum dosing regimen for rifapentine,will have to be determined by controlled clinical trials.