Wasserman, S., Davis, A., Stek, C., Chirehwa, M., Botha, S., Daroowala, R., Bremer, M., Maxebengula, M., Koekemoer, S., Goliath, R., Jackson, A., Crede, T., Naude, J., Szymanski, P., Vallie, Y., Moosa, M. S., Wiesner, L., Black, J., Meintjes, G., Maartens, G., … Wilkinson, R. J. (2021). Plasma Pharmacokinetics of High-Dose Oral versus Intravenous Rifampicin in Patients with Tuberculous Meningitis: a Randomized Controlled Trial. Antimicrobial agents and chemotherapy, 65(8), e0014021. https://doi.org/10.1128/AAC.00140-21
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/mm3 (interquartile range [IQR], 66 to 253 cells/mm3). The rifampicin geometric mean area under the concentration-time curve from 0 to 24 h (AUC0–24) values were 42.9mg · h/ml (95% confidence interval [CI], 24.5 to 75.0mg ·h/ml) for the standard dose, 295.2mg · h/ml (95% CI, 189.9 to 458.8mg · h/ml) for the high oral dose, and 206.5mg · h/ml (95% CI, 154.6 to 275.8mg · h/ml) for intravenous administration. The rifampicin AUC0–24 GMR was 1.44 (90% CI, 0.84 to 2.21) and the maximal concentration of drug in serum (Cmax) GMR was 0.89 (90% CI, 0.63 to 1.23) for high-dose oral administration with respect to intravenous dosing. The plasma rifampicin AUC0–24 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.