High-Dose Isoniazid Lacks EARLY Bactericidal Activity against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized Phase II Clinical Trial

Abstract

<b>Rationale:</b> Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>) with <i>katG</i> mutations (which typically confer high-level resistance) is not established. <b>Objectives:</b> To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by <i>katG</i>-mutated <i>M.tb</i>. <b>Methods:</b> A5312 was a phase IIA randomized, open-label trial. Participants with tuberculosis caused by <i>katG-</i>mutated <i>M.tb</i> 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, <i>inhA</i>-mutated, and <i>katG</i>-mutated <i>M.tb</i>). EBA was determined using nonlinear mixed-effects modeling. <b>Measurements and Main Results:</b> Of 80 treated participants, 21 had <i>katG</i>-mutated <i>M.tb</i>. 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 <i>katG</i>-mutated <i>M.tb</i> was approximately 10-fold lower than in <i>inhA</i>-mutated <i>M.tb</i>. The highest dose of 20 mg/kg did not demonstrate measurable EBA, except against a subset of slow <i>NAT2</i> acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. <b>Conclusions:</b> This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by <i>katG-</i>mutated <i>M.tb</i>. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).