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Am J Respir Crit Care Med ; 210(3): 343-351, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-38564365

RESUMO

Rationale: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established. Objectives: To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. Methods: A5312 was a phase IIA randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive pharmacokinetic sampling was performed on Day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modeling. Measurements and Main Results: Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid pharmacokinetics were best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived maximum concentration and area under the concentration-time curve in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg ⋅ h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal maximum efficacy relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than in inhA-mutated M.tb. The highest dose of 20 mg/kg did not demonstrate measurable EBA, except against a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. Conclusions: This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).


Assuntos
Antituberculosos , Proteínas de Bactérias , Isoniazida , Mutação , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Isoniazida/farmacocinética , Isoniazida/administração & dosagem , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Feminino , Masculino , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Adulto , Pessoa de Meia-Idade , Proteínas de Bactérias/genética , Catalase/genética , Relação Dose-Resposta a Droga , Idoso , Testes de Sensibilidade Microbiana
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