Plasma pharmacokinetics of high dose oral versus intravenous rifampicin in patients with tuberculous meningitis: a randomized controlled trial

BackgroundHigher 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 methodsWe 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).ResultsForty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; IV, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 −253). Geometric mean AUC0-∞ was 47.7 µg·h/mL (90% CI, 33.2 – 68.5) for standard dose; 322.3 µg·h/mL (90% CI,234.6 – 442.7) for high dose; and 214.6 µg·h/mL (90% CI, 176.2 – 261.2) for intravenous. High dose oral dosing achieved higher rifampicin exposure than intravenous: AUC0-∞ GMR 0.67 (90% CI, 0.46 −1.0); however, Cmax GMR was 1.11 (90% CI, 0.81 – 1.59), suggesting equivalence.ConclusionsPlasma rifampicin exposure was similar with high dose oral and intravenous administration. Findings support oral rifampicin dosing in future tuberculous meningitis trials.