Population pharmacokinetics and target attainment of pretomanid in rifampicin-resistant tuberculosis patients
Abstract
Abstract Pretomanid is a key component of the bedaquiline, pretomanid, linezolid with or without moxifloxacin (BPaL/M) regimen recommended for treatment of rifampicin-resistant tuberculosis (RR-TB). To support dose optimization and efficacy interpretation, we developed a pretomanid population pharmacokinetic (PK) model and evaluated exposure and probability of target attainment (PTA). Ninety-four RR-TB patients received daily oral pretomanid at 200 mg, and plasma samples were collected at multiple time points. Pretomanid concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry and PK modeling was performed using nlmixr2 in R. A one-compartment model with first-order absorption and elimination, and fat free mass allometric scaling best described the data. Typical clearance was 3.10 L/h (32.9%CV), median AUC₀₋₂₄ was 64,000 (31,000– 140,000) ng·h/ml, and the median maximum inter-dose concentration (Cmax) was 3,000 (1,000– 6,000) ng/ml. Pretomanid MICs for Mycobacterium tuberculosis in the TB-PRACTECAL trial were consistently below the provisional critical concentration, with a median of 0.125 mg/L. PK-Pharmacodynamic (PD) simulations indicated that nearly all participants achieved drug exposures exceeding %fT > MIC target, consistent with the regimen’s clinical efficacy across the study population. However, the AUC/MIC target was not achieved. We developed a pretomanid population PK model and facilitated exploring robustness of PK-PD targets for PTA. Our study confirmed the clinical relevance of the time dependent index and target, but further investigation is needed to determine whether the 167 AUC/MIC target is valid in patients or using translational pre-clinical experiments, especially within the context of combination therapy. Trial registry : Clinical Trials.gov, TRN: NCT04081077, Registration date: 4 September 2019.
Article Details
Authors (11)
Bern-Thomas Nyang’wa
Ilaria Motta
From Médecins Sans Frontières (L.G., F.V.), Sorbonne Université, INSERM Unité 1135, Centre d’Immunologie et des Maladies Infectieuses (L.G.), Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Universitaire Sorbonne Université, Hôpital Pitié–Salpêtrière, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (L.G.), and Epicentre (M.G., E. Baudin), Paris, and Translational Research on HIV and Endemic and Emerging Infectious Diseases, Montpellier Université de Montpellier, Montpellier, Institut de Recherche pour le Développement, Montpellier, INSERM, Montpellier (M.B.) — all in France; Interactive Development and Research, Singapore (U.K.); McGill University, Epidemiology, Biostatistics, and Occupational Health, Montreal (U.K.); UCSF Center for Tuberculosis (G.E.V., P.N., P.P.J.P.) and the Division of HIV, Infectious Diseases, and Global Medicine (G.E.V.), University of California at San Francisco, San Francisco; the National Scientific Center of Phth...
Ronelle Moodliar
Varvara Solodovnikova
Shakira Rajaram
Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg
Mohammed Rasool
Catherine Berry
From Médecins Sans Frontières (L.G., F.V.), Sorbonne Université, INSERM Unité 1135, Centre d’Immunologie et des Maladies Infectieuses (L.G.), Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Universitaire Sorbonne Université, Hôpital Pitié–Salpêtrière, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (L.G.), and Epicentre (M.G., E. Baudin), Paris, and Translational Research on HIV and Endemic and Emerging Infectious Diseases, Montpellier Université de Montpellier, Montpellier, Institut de Recherche pour le Développement, Montpellier, INSERM, Montpellier (M.B.) — all in France; Interactive Development and Research, Singapore (U.K.); McGill University, Epidemiology, Biostatistics, and Occupational Health, Montreal (U.K.); UCSF Center for Tuberculosis (G.E.V., P.N., P.P.J.P.) and the Division of HIV, Infectious Diseases, and Global Medicine (G.E.V.), University of California at San Francisco, San Francisco; the National Scientific Center of Phth...
Zhonghui Huang
Geraint Davies
David A.J. Moore
Frank Kloprogge