A semimechanistic model of the bactericidal activity of high-dose isoniazid against multidrug-resistant tuberculosis: Results from a randomized clinical trial

Kamunkhwala Gausi, Elisa H. Ignatius, Xin Sun, Soyeon Kim, Laura Moran, Lubbe Wiesner, Florian Von Groote-Bidlingmaier, Richard Hafner, Kathleen Donahue, Naadira Vanker, Susan L. Rosenkranz, Susan Swindells, Andreas H. Diacon, Eric L. Nuermberger, Kelly E. Dooley, Paolo Denti

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Rationale: There is accumulating evidence that higher-thanstandard doses of isoniazid are effective against low-tointermediate- level isoniazid-resistant strains of Mycobacterium tuberculosis, but the optimal dose remains unknown. Objectives: To characterize 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 (AIDS Clinical Trial Group) A5312/INHindsight is a 7-day early bactericidal activity study with isoniazid at a normal dose (5 mg/kg) for patients with drug-sensitive bacteria and 5, 10, and 15mg/kg doses for patients with inhA mutants. Participants with pulmonary tuberculosis received daily isoniazidmonotherapy and collected sputum daily. Colony-forming units (cfu) on solid culture and time to positivity in liquid culture were jointly analyzed using nonlinear mixed-effectsmodeling. Measurements and Main Results: Fifty-nine adults were included in this analysis. A decline in sputum cfu was described by a one-compartment model, whereas an exponential bacterial growth model was used to interpret time-to-positivity data. The model found that bacterial kill is modulated by isoniazid concentration using an effect compartment and a sigmoidal Emax relationship (a model linking the drug concentration to the observed effect). The model predicted lower potency but similar maximum kill of isoniazid against inhA-mutated compared with drug-sensitive isolates. Based on simulations from the pharmacokineticspharmacodynamics model, to achieve a drop in bacterial load comparable to 5 mg/kg against drug-sensitive tuberculosis, 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.

Original languageEnglish (US)
Pages (from-to)1327-1335
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume204
Issue number11
DOIs
StatePublished - Dec 1 2021

Keywords

  • Early bactericidal activity
  • InhA mutation
  • Isoniazid resistance
  • Phase 2 clinical trial
  • Tuberculosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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