A Semi-Mechanistic Model of the Bactericidal Activity of High-Dose Isoniazid Against Multi-Drug-Resistant Tuberculosis: Results from a Randomized Clinical Trial

Am J Respir Crit Care Med. 2021 Aug 17. doi: 10.1164/rccm.202103-0534OC. Online ahead of print.

Abstract

Rationale: There is accumulating evidence that higher-than-standard doses of isoniazid are effective against low-to-intermediate-level isoniazid-resistant strains of Mycobacterium tuberculosis, but the optimal dose remains unknown.

Objective: Characterizing the association between isoniazid pharmacokinetics (standard or high-dose) and early bactericidal activity against M. tuberculosis (drug-sensitive and inhA-mutated) and N-acetyltransferase 2 status.

Methods: ACTG A5312/INHindsight is 7-day early bactericidal activity study with isoniazid at normal dose (5 mg/kg) for patients with drug-sensitive bacteria and 5, 10, and 15 mg/kg doses for patients with inhA mutants. Participants with pulmonary TB received daily isoniazid monotherapy and collected sputum daily. Colony-forming units (CFU) on solid culture and time-to-positivity (TTP) in liquid culture were jointly analyzed using nonlinear mixed-effects modeling.

Results: Fifty-nine adults were included in this analysis. Decline in sputum CFU was described by a one-compartment model, while an exponential bacterial growth model was used to interpret TTP data. The model found bacterial kill is modulated by isoniazid concentration using an effect compartment and a sigmoidal Emax relationship. The model predicted lower potency but similar maximum-kill of isoniazid against inhA-mutated isolates compared to drug-sensitive. Based on simulations from the PK/PD model, to achieve a drop in bacterial load comparable to 5mg/kg against drug-sensitive TB, 10- and 15-mg/kg doses are necessary against inhA-mutated isolates in slow and intermediate N-acetyltransferase 2 acetylators, respectively. Fast acetylators underperformed even at 15 mg/kg.

Conclusions: Dosing of isoniazid based on N-acetyltransferase 2 acetylator status may help patients attain effective exposures against inhA-mutated isolates while mitigating toxicity risks associated with higher doses. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01936831.

Keywords: Early bactericidal activity; InhA mutation; Isoniazid resistance; Phase 2 clinical trial; Tuberculosis.

Associated data

  • ClinicalTrials.gov/NCT01936831