Comparative efficacy of rifapentine alone and in combination with isoniazid for latent tuberculosis infection: a translational pharmacokinetic-pharmacodynamic modelling study.

Abstract

Background Rifapentine has facilitated treatment shortening of latent tuberculosis infection (LTBI) in combination with isoniazid once weekly for 3 months (3HP) or daily for 1 month (1HP). Objective We determine the optimal rifapentine dose for a 6-week monotherapy regimen (6wP) and predict clinical efficacy. Methods Rifapentine and isoniazid pharmacokinetics were simulated in mice and humans. Mouse lung colony-forming unit data were used to characterize exposure-response relationships of 1HP, 3HP, and 6wP and translated to predict clinical efficacy. Results A 600 mg daily dose for 6wP delivered greater cumulative rifapentine exposure than 1HP or 3HP. The maximum regimen effect (Emax) was 0.24 day-1. The regimen potencies, measured as concentration at 50% of Emax (EC50), were estimated as 2.12 mg/L for 3HP, 3.72 mg/L for 1HP, and 4.71 mg/L for 6wP, suggesting that isoniazid contributes little to 1HP efficacy. Clinical translation predicted that 6wP reduces bacterial load at a faster rate than 3HP and a greater extent than 3HP and 1HP. Conclusions 6wP (600 mg daily) is predicted to result in equal or better efficacy than 1HP and 3HP for LTBI treatment without the potential added toxicity of isoniazid. Results from ongoing and future clinical studies will be required to support these findings.