Population Pharmacokinetic Analysis of Isoniazid among Pulmonary Tuberculosis Patients from China

Antimicrob Agents Chemother. 2020 Feb 21;64(3):e01736-19. doi: 10.1128/AAC.01736-19. Print 2020 Feb 21.

Abstract

The blood concentration of isoniazid (INH) is evidently affected by polymorphisms in N-acetyltransferase 2 (NAT2), an enzyme that is primarily responsible for the trimodal (i.e., fast, intermediate, and slow) INH elimination. The pharmacokinetic (PK) variability, driven largely by NAT2 activity, creates a challenge for the deployment of a uniform INH dosage in tuberculosis (TB) patients. Although acetylator-specific INH dosing has long been suggested, well-recognized dosages according to acetylator status remain elusive. In this study, 175 blood samples were collected from 89 pulmonary TB patients within 0.5 to 6 h after morning INH administration. According to their NAT2 genotypes, 32 (36.0%), 38 (42.7%), and 19 (21.3%) were fast, intermediate, and slow acetylators, respectively. The plasma INH concentration was detected by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic (PPK) analysis was conducted using NONMEM and R software. A two-compartment model with first-order absorption and elimination well described the PK parameters of isoniazid. Body weight and acetylator status significantly affected the INH clearance rate. The dosage simulation targeting three indicators, including the well-recognized efficacy-safety indicator maximum concentration in serum (Cmax; 3 to 6 μg/ml), the reported area under the concentration-time curve from 0 h to infinity (AUC0-∞; ≥10.52 μg·h/ml), and the 2-h INH serum concentrations (≥2.19 μg/ml), was associated with the strongest early bactericidal activity. The optimal dosages targeting the different indicators varied from 700 to 900 mg/day, 500 to 600 mg/day, and 300 mg/day for the rapid, intermediate, and slow acetylators, respectively. Furthermore, a PPK model for isoniazid among Chinese tuberculosis patients was established for the first time and suggested doses of approximately 800 mg/day, 500 mg/day, and 300 mg/day for fast, intermediate, and slow acetylators, respectively, after a trade-off between efficacy and the occurrence of side effects.

Keywords: China; NAT2; isoniazid; population pharmacokinetics; tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antitubercular Agents / blood
  • Antitubercular Agents / pharmacokinetics*
  • Antitubercular Agents / pharmacology
  • Area Under Curve
  • Arylamine N-Acetyltransferase / genetics*
  • Arylamine N-Acetyltransferase / metabolism
  • Asian People
  • Biotransformation
  • Body Weight
  • Chromatography, Liquid
  • Drug Administration Schedule
  • Female
  • Gene Expression
  • Genotype
  • Humans
  • Isoniazid / blood
  • Isoniazid / pharmacokinetics*
  • Isoniazid / pharmacology
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • Models, Statistical
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / growth & development
  • Prospective Studies
  • Tandem Mass Spectrometry
  • Tuberculosis, Pulmonary / drug therapy*
  • Tuberculosis, Pulmonary / ethnology
  • Tuberculosis, Pulmonary / genetics
  • Tuberculosis, Pulmonary / microbiology

Substances

  • Antitubercular Agents
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • Isoniazid