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

Sean Wasserman,Stephani Botha,Sonya Koekemoer,John Black,Marise Bremer,Yakoob Vallie,Amanda Jackson,Robert J Wilkinson,Graeme Meintjes,Lubbe Wiesner,Cari Stek,Patryk Szymanski,Gary Maartens,Angharad Davis,Thomas Crede,Remy Daroowala,Mpumi Maxebengula,Maxwell Chirehwa,Muhammed Shiraz Moosa ,René Goliath ,Jonathan Naudé

doi:10.1128/aac.00140-21

Abstract

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; intravenous, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 - 253). Rifampicin geometric mean AUC0-24 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 AUC0-24 GMR was 1.44 (90% CI, 0.84 - 2.21) and Cmax GMR was 0.89 (90% CI, 0.63 – 1.23) for high dose oral with respect to intravenous dosing.ConclusionsPlasma rifampicin AUC0-24 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.

Highlights

Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but are impractical in high-burden settings
Based on existing PK models of rifampicin [19, 20] and data showing equivalent area under the concentration-time curve (AUC) between 13 mg/kg given intravenously and 20 mg/kg given orally [17], we hypothesized that plasma rifampicin exposures will be similar between 35 mg/kg given orally and 20 mg/kg given intravenously, which has been proposed for efficacy trials in Tuberculous meningitis (TBM)
Forty-nine participants were enrolled in the parent trial, but 2 participants died, and 1 was withdrawn due to late exclusion prior to receiving the investigational product: 46 participants underwent intensive PK sampling and were included in this analysis (Fig. 1)

Summary

Introduction

Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but are impractical in high-burden settings. Existing population pharmacokinetic (PK) models can predict plasma rifampicin concentrations at doses of up to 40 mg/kg orally [19], but this has not been done for intravenous administration, where exposure is unaffected by the prehepatic first-pass effect [19]. This knowledge gap has important implications for TBM trials and the ultimate deployment of intensified antimicrobial therapy for TBM in resource-limited settings as intravenous rifampicin has limited availability, and its use will be associated with increased costs, hospitalizations, and complications relating to peripheral venous catheterization.

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Results

Conclusion