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

Abstract

Background: Accumulating data indicate that higher rifampicin doses are more effective and shorten tuberculosis (TB) 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 TB.

Methods: 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 days 8 and 14.

Results: In the 40 mg·kg^-1 cohort (n=15), 13 patients experienced a total of 36 adverse events during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg^-1 cohort (n=17), all patients experienced adverse events during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. Adverse events were mostly mild/moderate and tolerability rather than safety related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinaemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean area under the plasma concentration-time curve from time 0 to 12 h (AUC_{0-24 h}) for 50 mg·kg^-1 compared with 40 mg·kg^-1; 571 (range 320-995) versus 387 (range 201-847) mg·L^-1·h, while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg^-1 (11% (range 8-17%)) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (Spearman's ρ=0.670 on day 3, p<0.001). EBA increased considerably with dose, with the highest seen after 50 mg·kg^-1: 14-day EBA -0.427 (95% CI -0.500- -0.355) log₁₀CFU·mL^-1·day^-1.

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.

Trial registration: ClinicalTrials.gov NCT01392911.

FIGURE 1

a, b) 7- and c, d) 14-day early bactericidal activity (EBA) (95% CI) of rifampicin based on a, c) CFU and b, d) time to positivity (TTP). Data from all patients were included with the exception of data from one patient from each of the 20 and 50 mg·kg⁻¹ groups that had consistent negative cultures at baseline and throughout. The slight change in the estimates for 10 and 20 mg·kg⁻¹ compared with previously [6] are because of data corrections (four CFU cultures were recorded as negative while they were actually missing).

FIGURE 2

Total serum bilirubin per day on rifampicin plotted against rifampicin total exposures (area under the plasma concentration–time curve from time 0 to 12 h (AUC_0–24 h) at day 7) in all patients with pharmacokinetic results (n=93) in the HIGHRIF1 study. The lines represent linear regressions (for illustration; statistical testing described in the text). The y-axis is capped at 70 µmol·L⁻¹ for readability, excluding three outlying points (day 3 in one patient in the 40 mg·kg⁻¹ group with AUC_0–24 h 338 mg·L⁻¹·h and bilirubin 111 µmol·L⁻¹; day 7 and 10 in one patient in the 50 mg·kg⁻¹ group with AUC_0–24 h 980 mg·L⁻¹·h and bilirubin 100 and 175 µmol·L⁻¹, respectively).

FIGURE 3

Probability of tolerability-related adverse events during the first week of rifampicin monotherapy related to the rifampicin a) dose or b) exposure (area under the plasma concentration–time curve from time 0 to 12 h (AUC_0–24 h) at day 7). The shaded areas represent 90% confidence intervals based on the estimated parameter uncertainty