Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg⁻¹ rifampicin

Abstract

Accumulating data have indicated that higher rifampicin doses are more effective and shorten tuberculosis treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7 and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIGHRIF1, a dose-escalation study in treatment-naive adult smear-positive patients with tuberculosis. Patients received, in consecutive cohorts, 40 or 50 mg·kg−1 rifampicin once daily in monotherapy (day 1–7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between day 8–14. In the 40 mg·kg−1 cohort (n=15), 13 patients experienced a total of 36 adverse events (AEs) during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg−1 group (n=17), all patients experienced AEs during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. AEs were mostly mild/moderate and tolerability- rather than safety-related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean AUC0–24h for 50 mg·kg−1 compared to 40 mg·kg; 571 mg·L*h−1 (range 320–995) versus 387 mg·L*h−1 (201–847), while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg−1 (11%, 8–17%) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (day-3 Spearman's rho 0.670, p<0.001). EBA increased considerably with dose, with the highest seen after 50 mg·kg−1; 14-day EBA −0.427 logCFU·mL−1·day−1 (95%CI −0.500, −0.355). In conclusion, although associated with an increased bactericidal effect, the 50 mg·kg−1 dose was not well tolerated. Rifampicin at 40 mg·kg−1 was well tolerated and therefore selected for evaluation in a phase IIC treatment shortening trial.

Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness

“…To help design such studies, simulations were conducted for widely available dosages of each drug, with the highest median being 34 mg/kg of rifampin, 17 mg/kg of isoniazid, 57 mg/kg of pyrazinamide, and 45 mg/kg of ethambutol. Recent trials have demonstrated a tolerable use of higher doses of rifampin up to 40 mg/kg in pulmonary TB patients with mild to moderate related adverse effects [ 28 , 29 , 30 ]. Similarly, patients treated with higher isoniazid doses between 15 and 20 mg/kg have had improved outcomes with faster culture conversion in rifampin-resistant anti-TB regimens [ 31 ], yet the essentiality of isoniazid has been more difficult to demonstrate for rifampin-susceptible TB [ 32 ].…”

Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP)

“…11 Rifampicin 40 mg/kg was recently identified as the highest tolerated dose with dose limiting factors reported as gastrointestinal disorders, pruritus, hyperbilirubinaemia and jaundice. 26 However, the safety of simultaneously administered high-dose pyrazinamide and rifampicin remains to be explored. Our study aims to investigate PK-PD data, safety and tolerability of a 4-month first-line treatment with combined high dosing of pyrazinamide and rifampicin to a selected group of patients with non-advanced pulmonary TB.…”

“…11 Furthermore, data were recently presented on exposure-tolerability of 2 weeks treatment with rifampicin 40 mg/kg (n=15) and 50 mg/kg (n=17) where the dose of 40 mg/kg was safe and tolerable. 26 In early studies on lengthy treatments of pyrazinamide beyond 8 weeks, increased liver markers, jaundice and arthralgia were associated with higher doses of pyrazinamide. 51 In a meta-analysis comparing rates of AEs between different doses of pyrazinamide, the frequencies of hepatotoxicity were 0.042 (95% CI 0.026 to 0.067) for 30 mg/kg, 0.055 (95% CI 0.031 to 0.094) for 40 mg/kg and 0.098 (95% CI 0.047 to 0.193) for 60 mg/kg, suggesting a considerable proportion of hepatoxicity rates may be idiosyncratic rather than dose-dependent.…”

“…Rifampicin doses of at least three times the standard dose combined with isoniazid, pyrazinamide and ethambutol was safely administered to 63 patients with pulmonary TB for 12 weeks 11. Rifampicin 40 mg/kg was recently identified as the highest tolerated dose with dose limiting factors reported as gastrointestinal disorders, pruritus, hyperbilirubinaemia and jaundice 26. However, the safety of simultaneously administered high-dose pyrazinamide and rifampicin remains to be explored.…”

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

“…However, rifampicin is highly protein-bound (6) and the cerebrospinal (CSF) penetration of total drug is poor (7), rarely exceeding the minimum inhibitory concentration of M. tuberculosis (8)(9)(10). Studies in pulmonary TB have shown that bactericidal activity is related to rifampicin area under the concentration-time curve (AUC) (11,12) and that microbiological outcomes are improved at higher doses, up to 40 mg/kg (13)(14)(15). A small randomized controlled trial showed survival benefit with the use of intravenous rifampicin 13 mg/kg for Indonesian adults with TBM (16), which had similar plasma exposures to oral rifampicin 20 mg/kg (17).…”