Single-Dose Intrapulmonary Pharmacokinetics of Rifapentine in Normal Subjects

Abstract

The intrapulmonary pharmacokinetics of rifapentine were studied in 30 volunteers who received a single, oral dose of rifapentine (600 mg). Subgroups of five subjects each underwent bronchoscopy and bronchoalveolar lavage (BAL) at timed intervals following drug administration. Drug concentrations, including the concentration of the primary metabolite 25-desacetyl rifapentine, were determined in plasma, BAL fluid, and alveolar cells (AC) by high-pressure 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 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, and AC were 18.3 h and 520 g ⅐ h/ml, 20.8 h and 111 g ⅐ h/ml, and 13.0 h and 133 g ⅐ h/ml, respectively. Although the intrapulmonary rifapentine concentrations were less than the plasma rifapentine concentrations at all time periods, they remained above the proposed breakpoint for M. tuberculosis (0.5 g/ml) for the 48-h observation period. These data provide a pharmacokinetic rationale for extended-interval dosing. The optimum dosing regimen for rifapentine will have to be determined by controlled clinical trials.Rifapentine is an orally administered rifamycin derivative that has antituberculous activity and that is similar to rifampin (11,12,16,27). The MICs for sensitive strains are usually in the range of 0.03 to 0.12 mg/liter, and MICs for resistant strains are Ն8 mg/liter (15). Cross-resistance between rifapentine and rifampin is virtually complete (15). Cross-resistance between rifapentine and rifampin is virtually complete (15). Rifapentine has a longer elimination half-life than rifampin, allowing the possibility of less frequent (twice-or once-weekly) administration (17).There have been no previous reports of the intrapulmonary concentrations or pharmacokinetics of rifapentine in humans. The purpose of this study was to compare the concentrations of rifapentine in plasma, alveolar cells (ACs), and epithelial lining fluid (ELF) of normal volunteers and to compare the drug's pharmacokinetics in these three compartments. MATERIALS AND METHODSSubjects. The protocol was approved by the Human Research Committee of the University of California, San Francisco. Written informed consent was obtained from each subject by an experienced research nurse. Subjects were required to be 18 to 45 years of age. If the subjects were female, they were required to be nonlactating and not pregnant and to agree to use adequate contraception (e.g., barrier methods or abstinence) during the study and for 2 weeks following completion of the study. Women using oral contraceptives were required to agree to use a barrier method in addition for 1 month following the study. Subjects who were lactating or pregnant, had a history of intolerance to rifamycin dr...

Intrapulmonary Pharmacokinetics of Linezolid

“…Researchers (1)(2)(3)(4)(5)(8)(9)(10)(11)(12)(13) have developed techniques for the measurement, in vivo, of the concentrations of drugs in ELF and AC. The purpose of this study was to determine the steady-state intrapulmonary concentrations and intrapulmonary pharmacokinetic parameters of orally administered linezolid in healthy volunteers.…”

Augmenting Effect of Antibiotics on Endotoxin Activity May Cause a Safety Problem

“…The EID or ODD concept of antibiotics has been widely accepted according to the results of intensive studies on pharmacokinetic characteristics of antibiotics (2,10,16,17). ODD uses an increased dose for the daily shot and is reported to have an improved efficacy due to concentration-dependent bactericidal activity and also is suggested to minimize the likelihood of developing toxicities comparing to the traditional multiple daily dosing (1,14).…”

Poster Abstracts

“…It is noteworthy that the Cmax, Tmax values in plasma derived from this study were very similar to those reported in earlier studies with previous reports. (19)(20)(21). These data confirm that the high peak concentration of moxifloxacin also appears to result in a high intrapulmonary concentration, i.e., 2651.86 ± 560.42 mg/mL in AMs and 502.07 ± 131.99 mg/mL in ELF.…”

“…[16][17][18][19][20][21][22][23] The volume of ELF contained in each BALf sample was determined by the urea dilution method. Urea diffuses freely throughout the body with the concentration in plasma equal to that in other body fluids.…”

“…After administration of corticosteroids, the reduction of IL-4 occurs that effect on synthesis of IgE. In current study, evaluation of the effect of treatment was performed after 2 weeks, because as van der Woude et al reported that, there was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment (19). In COPD patients with elevated IgE, atopy or sputum eosinophilia, they will form a subgroup of patients with better prognosis and a greater likelihood of corticosteroid responsiveness (20).…”