Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2026
Pharmacokinetic and pharmacogenomic predictors of hepatotoxicity in the HIRIF trial for drug-susceptible tuberculosis.
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Yang Eunsol, Van Brantegem Pieter, Peloquin Charles A, Brooks Meredith B, Coit Julia M, Vargas Vásquez Dante, Sánchez Garavito Epifanio, Calderón Roger I, Jiménez Judith, Tintaya Karen, Garcia Dalicxa, Osso Elna, Mackay Elizabeth A, Platt Gareth, Lecca Leonid, Savic Radojka M, Davies Geraint R, Mitnick Carole D, Velásquez Gustavo E
Аннотация
BACKGROUND: Hepatotoxicity is frequent in the standard-of-care regimen for drug-susceptible tuberculosis, yet the association of each companion drug with hepatotoxicity has not been fully characterized. We examined the association between hepatotoxicity and the pharmacokinetics of rifampin and its companion drugs in standard therapy, as well as N-acetyltransferase 2 (NAT2) genotype.
METHODS: We evaluated HIRIF trial participants who were randomized to receive rifampin 10, 15, or 20 mg/kg/day during the intensive phase of tuberculosis treatment. We fitted Cox proportional hazards models to identify risk factors for grade 2 or higher (grade 2+) alanine transaminase (ALT) or aspartate transaminase (AST) elevation, and considered pharmacokinetic exposure of each antituberculosis drug and NAT2 genotype as potential covariates.
RESULTS: Among 168 participants with pharmacokinetic data, neither rifampin dose nor exposure were associated with the risk of grade 2+ ALT or AST elevation. Higher pyrazinamide exposure (hazard ratio [HR] 1.85 for every 50 mg*h/L AUC0-6h increase), higher isoniazid exposure (HR 1.40 for every 5 mg*h/L AUC0-6h increase), and among a subset with known NAT2 genotype, slow NAT2 acetylator status (HR 9.32 relative to fast, n=90) were associated with grade 2+ ALT or AST elevation in univariable analysis. In multivariable analysis, only pyrazinamide exposure was associated with hepatotoxicity.
CONCLUSIONS: While higher pyrazinamide and isoniazid exposures and slow NAT2 acetylator status were each associated with increased hepatotoxicity, only pyrazinamide exposure was associated when considering pharmacokinetic variables together. Rifampin exposure was not associated with hepatotoxicity, supporting further evaluation of doses up to 20 mg/kg/day in a larger trial.
METHODS: We evaluated HIRIF trial participants who were randomized to receive rifampin 10, 15, or 20 mg/kg/day during the intensive phase of tuberculosis treatment. We fitted Cox proportional hazards models to identify risk factors for grade 2 or higher (grade 2+) alanine transaminase (ALT) or aspartate transaminase (AST) elevation, and considered pharmacokinetic exposure of each antituberculosis drug and NAT2 genotype as potential covariates.
RESULTS: Among 168 participants with pharmacokinetic data, neither rifampin dose nor exposure were associated with the risk of grade 2+ ALT or AST elevation. Higher pyrazinamide exposure (hazard ratio [HR] 1.85 for every 50 mg*h/L AUC0-6h increase), higher isoniazid exposure (HR 1.40 for every 5 mg*h/L AUC0-6h increase), and among a subset with known NAT2 genotype, slow NAT2 acetylator status (HR 9.32 relative to fast, n=90) were associated with grade 2+ ALT or AST elevation in univariable analysis. In multivariable analysis, only pyrazinamide exposure was associated with hepatotoxicity.
CONCLUSIONS: While higher pyrazinamide and isoniazid exposures and slow NAT2 acetylator status were each associated with increased hepatotoxicity, only pyrazinamide exposure was associated when considering pharmacokinetic variables together. Rifampin exposure was not associated with hepatotoxicity, supporting further evaluation of doses up to 20 mg/kg/day in a larger trial.