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

Abstract

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/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. Conclusions Plasma 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.

Intensified Antituberculosis Therapy Regimen Containing Higher Dose Rifampin for Tuberculous Meningitis: A Systematic Review and Meta-Analysis

“…The study conducted by Wasserman and colleagues also had two intervention groups, which received either high-dose oral rifampin at 35 mg/kg/day or intravenously at 20 mg/kg/day. It had a low risk of performance and detection bias as the outcome measure was an objective PK endpoint; we found that lack of participant blinding could not have significantly affected the outcome (13). In summary, all the included studies had a low risk of selection, attribution, and other bias.…”

“…In two studies the intensified regimen involved quinolones, one of them containing levofloxacin at 20 mg/kg/day (11), while another one included moxifloxacin at 400 mg/day or 800 mg/day (10). And in one study from Sean Wasserman, the intervention group treatment consisted of high-dose rifampin plus linezolid, as well as other first-line antituberculosis drugs, one intervention arm applied aspirin at the same time (13). For the method of rifampin concentration detection, in a study by Ruslami (10), rifampin concentration was analyzed by validating high performance liquid chromatography assays (HPLC).…”

“…For the method of rifampin concentration detection, in a study by Ruslami (10), rifampin concentration was analyzed by validating high performance liquid chromatography assays (HPLC). The liquid chromatography-tandem mass spectrometry assay was performed to measure the rifampin concentration in two studies by Wasserman and Ding (13,14). In addition, Cresswell et al (15) used high-performance liquid chromatography with ultraviolet detection (HPLC-UV) to measure the concentration of rifampin in plasma and CSF.…”

“…The trials reported by Wasserman and Dian (13,16) had an unclear risk of allocation concealment due to missing data. The studies conducted by Heemskerk et al (11,14,16) had an unclear risk of detection bias as they did not clearly illustrate the method used in personnel and outcome assessments.…”

“…Four eligible studies reported the plasma C max of rifampin (10,13,15,16). The random effects model meta-analysis showed that there were significant differences in plasma rifampin C max 3].…”