Plasma Pharmacokinetics of High-Dose Oral versus Intravenous Rifampicin in Patients with Tuberculous Meningitis: a Randomized Controlled Trial

Background Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis. Materials and methods 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 (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR). Results Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; intravenous, n = 14). Median CD4 count was 130 cells/mm 3 (IQR 66 - 253). Rifampicin geometric mean AUC 0-24 was 42.9 μg.h/mL (95% CI, 24.5 – 75.0) for standard dose; 295.2 μg.h/mL (95% CI, 189.9 – 458.8) for high dose oral; and 206.5 μg-h/mL (95% CI, 154.6 – 275.8) for intravenous administration. Rifampicin AUC 0-24 GMR was 1.44 (90% CI, 0.84 - 2.21) and C max GMR was 0.89 (90% CI, 0.63 – 1.23) for high dose oral with respect to intravenous dosing. Conclusions Plasma rifampicin AUC 0-24 was higher after an oral 35 mg/kg dose compared with intravenous administration at 20 mg/kg dose over the first few days of TB treatment. Findings support oral rifampicin dosing in future tuberculous meningitis trials.