Genotype-guided isoniazid dosing harmonizes drug exposure in 3HP tuberculosis preventive therapy
- 1Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA
Abstract
RationalePolymorphisms in the N-acetyltransferase 2 (NAT2) gene explain much of the interindividual variation in isoniazid (INH) metabolism and determine risk of toxicities. However, there is limited evidence to guide INH dose adjustment according to the NAT2 acetylator profile in weekly rifapentine-INH tuberculosis preventive therapy (TPT).
ObjectivesWe evaluated whether NAT2 genotype-guided INH dose adjustment harmonizes drug exposure across acetylator phenotypes during 3HP and derived phenotype-specific dose recommendations.
MethodsIn a prospective, multicenter, within-subject PK trial (NCT05413551), adults initiating 3HP in Brazil were assigned genotype-guided INH doses (slow: 5 mg/kg [≤]300 mg; intermediate: 15 mg/kg [≤]900 mg; rapid: 25 mg/kg [≤]1,500 mg) alongside a standard 900 mg flat dose on an alternate occasion. AUC0-24 and C24 were estimated from serial blood samples; a two-compartment Michaelis-Menten population PK model characterized NAT2 effects on clearance.
Measurements and Main ResultsAmong 228 participants, 47.4% (108/228) were intermediate, 43.4% (99/228) slow, and 9.2% (21/228) rapid acetylators. Genotype-guided dosing reduced AUC0-24 variability approximately two-fold versus standard dosing (CV 58.8% vs 76.8%) and increased exposure uniformity (median AUC0- 24 27.2 [IQR 18.8-41.3] vs 43.2 [27.3-71.0] mg{middle dot}h/L). Among slow acetylators, C24 >0.15 {micro}g/mL decreased from 27/42 (64%) with standard dosing to 1/42 (2%) with genotype-guided dosing (P<0.0001). In 104 participants with intensive PK sampling, rapid acetylators receiving guided doses had AUC0-24similar to standard-dose intermediate acetylators (42.8 vs 39.5 mg{middle dot}h/L; P=.63). Monte Carlo simulations supported doses of 600, 900, and 1,200 mg for slow, intermediate, and rapid acetylators, respectively.
ConclusionsNAT2-guided isoniazid dosing reduced variation in drug levels, averting very low and high AUC and C24. These findings inform genotype-stratified dosing of INH for TPT, which might reduce toxicities and improve outcomes.
Related
- The Impact of Isoniazid Preventive Therapy on Tuberculosis Infection and Disease Progression
- The Blind Spot of GeneXpert MTB/RIF: Isoniazid‐Resistant, Rifampicin‐Susceptible Tuberculosis Detected on Phenotypic Drug Susceptibility Testing
- The effect of metformin on the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide in adults with tuberculosis
- Isoniazid monotherapy for tuberculosis prevention during pregnancy and adverse outcomes in women living with HIV in Uganda: A propensity score–weighted analysis of routine care data
- Real-world evaluation of the FluoroType MTBDR 2.0 assay for detection of rifampicin and isoniazid resistance-conferring mutations in Mycobacterium tuberculosis complex clinical isolates
BibTeX
@misc{silva2026genotypeguided,
title = {{Genotype-guided isoniazid dosing harmonizes drug exposure in 3HP tuberculosis preventive therapy}},
author = {K. da Silva and S. Sarkodie and K. Marques and P. Vieira and R. D. d. Oliveira and P. C. Pereira dos Santos and M. A. Moreira Puga and A. G. Costa and J. P. Gregorio Machado and R. Spener-Gomes and E. Yang and R. Savic and M. Cordeiro-Santos and J. Croda and J. R. Andrews},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.27.26360825},
url = {https://www.medrxiv.org/content/10.64898/2026.08.27.26360825v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Genotype-guided isoniazid dosing harmonizes drug exposure in 3HP tuberculosis preventive therapy
AU - K. da Silva
AU - S. Sarkodie
AU - K. Marques
AU - P. Vieira
AU - R. D. d. Oliveira
AU - P. C. Pereira dos Santos
AU - M. A. Moreira Puga
AU - A. G. Costa
AU - J. P. Gregorio Machado
AU - R. Spener-Gomes
AU - E. Yang
AU - R. Savic
AU - M. Cordeiro-Santos
AU - J. Croda
AU - J. R. Andrews
PY - 2026
DA - 2026/08/27
PB - medRxiv
DO - 10.64898/2026.08.27.26360825
UR - https://www.medrxiv.org/content/10.64898/2026.08.27.26360825v1
AB - RationalePolymorphisms in the N-acetyltransferase 2 (NAT2) gene explain much of the interindividual variation in isoniazid (INH) metabolism and determine risk of toxicities. However, there is limited evidence to guide INH dose adjustment according to the NAT2 acetylator profile in weekly rifapentine-INH tuberculosis preventive therapy (TPT). ObjectivesWe evaluated whether NAT2 genotype-guided INH dose adjustment harmonizes drug exposure across acetylator phenotypes during 3HP and derived phenotype-specific dose recommendations. MethodsIn a prospective, multicenter, within-subject PK trial (NCT05413551), adults initiating 3HP in Brazil were assigned genotype-guided INH doses (slow: 5 mg/kg [≤]300 mg; intermediate: 15 mg/kg [≤]900 mg; rapid: 25 mg/kg [≤]1,500 mg) alongside a standard 900 mg flat dose on an alternate occasion. AUC0-24 and C24 were estimated from serial blood samples; a two-compartment Michaelis-Menten population PK model characterized NAT2 effects on clearance. Measurements and Main ResultsAmong 228 participants, 47.4% (108/228) were intermediate, 43.4% (99/228) slow, and 9.2% (21/228) rapid acetylators. Genotype-guided dosing reduced AUC0-24 variability approximately two-fold versus standard dosing (CV 58.8% vs 76.8%) and increased exposure uniformity (median AUC0- 24 27.2 [IQR 18.8-41.3] vs 43.2 [27.3-71.0] mg{middle dot}h/L). Among slow acetylators, C24 >0.15 {micro}g/mL decreased from 27/42 (64%) with standard dosing to 1/42 (2%) with genotype-guided dosing (P<0.0001). In 104 participants with intensive PK sampling, rapid acetylators receiving guided doses had AUC0-24similar to standard-dose intermediate acetylators (42.8 vs 39.5 mg{middle dot}h/L; P=.63). Monte Carlo simulations supported doses of 600, 900, and 1,200 mg for slow, intermediate, and rapid acetylators, respectively. ConclusionsNAT2-guided isoniazid dosing reduced variation in drug levels, averting very low and high AUC and C24. These findings inform genotype-stratified dosing of INH for TPT, which might reduce toxicities and improve outcomes.
ER -