A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy

Antimicrob Agents Chemother. 2016 Sep 23;60(10):6134-45. doi: 10.1128/AAC.00508-16. Print 2016 Oct.

Abstract

Due to its high early bactericidal activity, isoniazid (INH) plays an essential role in tuberculosis treatment. Genetic polymorphisms of N-acetyltransferase type 2 (NAT2) cause a trimodal distribution of INH pharmacokinetics in slow, intermediate, and fast acetylators. The success of INH-based chemotherapy is associated with acetylator and patient health status. Still, a standard dose recommended by the FDA is administered regardless of acetylator type or immune status, even though adverse effects occur in 5 to 33% of all patients. Slow acetylators have a higher risk of development of drug-induced toxicity, while fast acetylators and immune-deficient patients face lower treatment success rates. To mechanistically assess the trade-off between toxicity and efficacy, we developed a physiologically based pharmacokinetic (PBPK) model describing the NAT2-dependent pharmacokinetics of INH and its metabolites. We combined the PBPK model with a pharmacodynamic (PD) model of antimycobacterial drug effects in the lungs. The resulting PBPK/PD model allowed the simultaneous simulation of treatment efficacies at the site of infection and exposure to toxic metabolites in off-target organs. Subsequently, we evaluated various INH dosing regimens in NAT2-specific immunocompetent and immune-deficient virtual populations. Our results suggest the need for acetylator-specific dose adjustments for optimal treatment outcomes. A reduced dose for slow acetylators substantially lowers the exposure to toxic metabolites and thereby the risk of adverse events, while it maintains sufficient treatment efficacies. Vice versa, intermediate and fast acetylators benefit from increased INH doses and a switch to a twice-daily administration schedule. Our analysis outlines how PBPK/PD modeling may be used to design and individualize treatment regimens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Antitubercular Agents / blood
  • Antitubercular Agents / pharmacokinetics*
  • Arylamine N-Acetyltransferase / genetics
  • Arylamine N-Acetyltransferase / metabolism*
  • Biological Availability
  • Biotransformation
  • Computer Simulation
  • Drug Administration Schedule
  • Drug Dosage Calculations
  • Gene Expression
  • Genotype
  • Humans
  • Immunity, Innate
  • Immunocompromised Host*
  • Isoniazid / blood
  • Isoniazid / pharmacokinetics*
  • Lung / drug effects
  • Lung / immunology
  • Lung / microbiology
  • Models, Statistical*
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / immunology
  • Polymorphism, Genetic
  • Precision Medicine
  • Tuberculosis, Pulmonary / blood
  • Tuberculosis, Pulmonary / drug therapy*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / microbiology

Substances

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

Grant support

This work was funded by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602156. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.