Safety, Efficacy, and Pharmacokinetics of Daily Optimized Doses of Rifampicin for the Treatment of Tuberculosis: A Systematic Review and Bayesian Network Meta-Analysis

Background: Higher than standard doses of rifampicin could improve the treatment outcome of drug-susceptible tuberculosis (TB) without compromising the safety of patients. Methods: We performed a systematic review of prospective clinical studies including adults with pulmonary and extrapulmonary TB receiving rifampicin doses above 10 mg/kg/day. We extracted the data on overall adverse events (AE), hepatic AE, sputum culture conversion (SCC) at week 8, recurrence, mortality, and pharmacokinetics. We performed a Bayesian network meta-analysis (NMA) using a random-effects model. Results: In 19 studies, 2033 out of 3654 participants received rifampicin doses higher than 10 mg/kg/day. The NMA showed an increased risk of overall and hepatic AE for the 40 mg/kg/day dose (risk ratio [RR] 4.8, 95% credibility interval [CrI]: 1.1, 25, and 15.00; 95% CrI: 1.1, 58.0, respectively), but no other doses, including 50 mg/kg/day showed such an increase. Increasing doses improved sputum culture conversion at week 8 (RR 1.3, 95% CrI: 1.1, 1.7 for SCC with 35 mg/kg/day). Conclusions: Optimal doses of rifampicin may be between 25 and 35 mg/kg/day, but should be tailored at the individual or, at least, at the population level.