期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 65, 期 8, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00140-21
关键词
human immunodeficiency virus; pharmacokinetics; rifampicin; tuberculous meningitis
资金
- European & Developing Countries Clinical Trials Partnership [CDF1018]
- Wellcome Trust [098316, 214321/Z/18/Z, 203135/Z/16/Z, 104803]
- National Institutes of Health [K43TW011421]
- Programme for Clinicians fellowship [175479]
- South African Research Chairs Initiative of the Department of Science and Technology
- National Research Foundation (NRF) of South Africa [64787]
- Francis Crick Institute [FC0010218]
- Meningitis Now
- NIH [R01AJ145436]
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health [UM1 AI068634, UM1 AI068636, UM1 AI106701]
The plasma rifampicin AUC(0-24) was higher after an oral 35-mg/kg dose than with intravenous administration at a 20-mg/kg dose over the first few days of tuberculosis (TB) treatment. The findings support oral rifampicin dosing in future tuberculous meningitis trials.
Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but are impractical in high-burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral dosing of 35 mg/kg of body weight and intravenous dosing of 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis. We performed a randomized parallel-group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using noncompartmental analysis, and exposures were compared by geometric mean ratios (GMRs). Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high-dose oral, n = 15; intravenous, n = 14). The median CD4 count was 130 cells/mm(3) (interquartile range [IQR], 66 to 253 cells/mm(3)). The rifampicin geometric mean area under the concentration-time curve from 0 to 24 h (AUC(0-24)) values were 42.9 mu g . h/ml (95% confidence interval [CI], 24.5 to 75.0 mu g . h/ml) for the standard dose, 295.2 mu g . h/ml (95% CI, 189.9 to 458.8 mu g . h/ml) for the high oral dose, and 206.5 mu g . h/ml (95% CI, 154.6 to 275.8 mu g . h/ml) for intravenous administration. The rifampicin AUC(0-24) GMR was 1.44 (90% CI, 0.84 to 2.21) and the maximal concentration of drug in serum (C-max) GMR was 0.89 (90% CI, 0.63 to 1.23) for high-dose oral administration with respect to intravenous dosing. The plasma rifampicin AUC(0-24) was higher after an oral 35-mg/kg dose than with intravenous administration at a 20-mg/kg dose over the first few days of tuberculosis (TB) treatment. The findings support oral rifampicin dosing in future tuberculous meningitis trials.
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