Model-based analysis of bactericidal activity and a new dosing strategy for optimised-dose rifampicin

Abstract

Higher doses of rifampicin for tuberculosis have shown to improve early bactericidal activity (EBA) but at the same time increase the intolerability due to high exposure in the beginning of treatment. In order to support dose optimization of rifampicin, we investigated a new and innovative staggered dosing of rifampicin using clinical trial simulations to minimize tolerability problems and still achieving a high efficacy. Rifampicin population pharmacokinetics and time-to-positivity models were applied to data from patients receiving 14 days of daily 10-50 mg/kg to characterize the exposure-response relationship. Furthermore, clinical trial simulations of rifampicin exposure was performed following four different staggered dosing scenarios. The simulated exposure after 35 mg/kg was used as relative comparison for efficacy. Tolerability was derived from a previous model-based analysis relating exposure at day 7 and the probability of having adverse events. Linear relationship between rifampicin exposure and bacterial killing rate in sputum indicated that the maximum rifampicin EBA was not reached at doses up to 50 mg/kg. Clinical trial simulations of a staggered dosing strategy with initializing the treatment at a lower dose (20 mg/kg) for 7 days followed by a higher dose (40 mg/kg) predicted a lower initial exposure with lower probability of tolerability problems and better EBA compared to a regimen of 35 mg/kg daily. Staggered dosing of 20 mg/kg for 7 days followed by 40 mg/kg is predicted to reduce tolerability while maintaining exposure levels associated with better efficacy.