We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
A Semimechanistic Model of the Bactericidal Activity of High-Dose Isoniazid against Multidrug-Resistant Tuberculosis: Results from a Randomized Clinical Trial.
- Authors
Gausi, Kamunkhwala; Ignatius, Elisa H.; Xin Sun; Soyeon Kim; Moran, Laura; Wiesner, Lubbe; von Groote-Bidlingmaier, Florian; Hafner, Richard; Donahue, Kathleen; Vanker, Naadira; Rosenkranz, Susan L.; Swindells, Susan; Diacon, Andreas H.; Nuermberger, Eric L.; Dooley, Kelly E.; Denti, Paolo; Sun, Xin; Kim, Soyeon
- 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. 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 15 mg/kg doses for patients with inhA mutants. Participants with pulmonary tuberculosis received daily isoniazid monotherapy and collected sputum daily. Colony-forming units (cfu) on solid culture and time to positivity in liquid culture were jointly analyzed using nonlinear mixed-effects modeling. 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 pharmacokinetics-pharmacodynamics 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. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).
- Subjects
ISONIAZID; MYCOBACTERIUM tuberculosis; PHARMACOKINETICS; TUBERCULOSIS; BACTERICIDAL action; TUBERCULOSIS microbiology; SPUTUM microbiology; DRUG therapy for tuberculosis; BACTERIAL proteins; RESEARCH; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; RANDOMIZED controlled trials; ANTITUBERCULAR agents; TRANSFERASES; DOSE-effect relationship in pharmacology; BACTERIAL growth; MICROBIOLOGICAL techniques; RESEARCH funding; OXIDOREDUCTASES; MICROBIAL sensitivity tests
- Publication
American Journal of Respiratory & Critical Care Medicine, 2021, Vol 204, Issue 11, p1327
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.202103-0534OC