TY - JOUR
T1 - A semimechanistic model of the bactericidal activity of high-dose isoniazid against multidrug-resistant tuberculosis
T2 - Results from a randomized clinical trial
AU - Gausi, Kamunkhwala
AU - Ignatius, Elisa H.
AU - Sun, Xin
AU - Kim, Soyeon
AU - Moran, Laura
AU - Wiesner, Lubbe
AU - Von Groote-Bidlingmaier, Florian
AU - Hafner, Richard
AU - Donahue, Kathleen
AU - Vanker, Naadira
AU - Rosenkranz, Susan L.
AU - Swindells, Susan
AU - Diacon, Andreas H.
AU - Nuermberger, Eric L.
AU - Dooley, Kelly E.
AU - Denti, Paolo
N1 - Funding Information:
Supported by TASK Applied Sciences grant #UM1AI069521; the National Center for Medical Rehabilitation Research grant AI068632; and the Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH grant U01 AI068632. The University of Cape Town Clinical PK Laboratory is supported in part via the AIDS Clinical Trial Group; by the National Institute of Allergy and Infectious Diseases of the NIH under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701; and the Infant Maternal Pediatric Adolescent AIDS Clinical Trials Group. E.H.I. is supported by T32 GM066691-17 and K.E.D. is supported by K24AI150349 both from the National Institute of Allergy and Infectious Diseases of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2021 American Thoracic Society. All rights reserved.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - Early bactericidal activity
KW - InhA mutation
KW - Isoniazid resistance
KW - Phase 2 clinical trial
KW - Tuberculosis
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U2 - 10.1164/rccm.202103-0534OC
DO - 10.1164/rccm.202103-0534OC
M3 - Article
C2 - 34403326
AN - SCOPUS:85121141161
SN - 1073-449X
VL - 204
SP - 1327
EP - 1335
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 11
ER -