Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg<sup>−1</sup>rifampicin
Lindsey H. M. te Brake, Veronique de Jager, Kim Narunsky, Naadira Vanker, Elin M. Svensson, Patrick Phillips, Stephen H. Gillespie, Norbert Heinrich, Michael Höelscher, Rodney Dawson, Andreas H. Diacon, Rob E. Aarnoutse, Martin J. Boeree
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) log 10 CFU·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.