A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators

Hyounggyoon Yoo, Sang Chun Ji, Joo Youn Cho, Sang Heon Kim, Jihoon G. Yoon, Min Goo Lee, Kyung Sang Yu, In Jin Jang, Jaeseong Oh

Research output: Contribution to journalArticlepeer-review

Abstract

Isoniazid is a therapeutic agent for the treatment of latent tuberculosis infection. Genetic variants in the N-acetyltransferase 2 (NAT2) are associated with the safety and pharmacokinetics of isoniazid. The study aimed to evaluate the safety and pharmacokinetics of a NAT2 genotype-guided regimen of isoniazid monotherapy. A randomized, open-label, parallel-group and multiple-dosing study was performed in healthy subjects. The subjects received isoniazid for 29 days. The NAT2 slow acetylators (NAT2∗5/∗5,-∗5/∗6,-∗5/∗7,-∗6/∗6,-∗6/∗7,-∗7/∗7) randomly received standard dose (300 mg, standard-treatment group) or reduced dose (200 mg, PGx-treatment group) of isoniazid. Also, all the NAT2 rapid acetylators (NAT2∗4/∗4) received isoniazid 300 mg (reference group). The safety and pharmacokinetics were evaluated during the study. The PGx-treatment group showed a more stable serum liver enzyme profile and a lower incidence of adverse drug reactions (ADRs) than the standard-treatment group. The emergence rates of ADRs were 12.5, 60 and 33.3% in the reference, standard-treatment and PGx-treatment groups, respectively. The PGx-treatment group showed higher plasma isoniazid concentrations than the reference group, although the PGx-treatment group received a reduced dose of isoniazid. Our results showed that a NAT2 genotype-guided regimen may reduce ADRs during isoniazid monotherapy without concern over insufficient drug exposure.

Original languageEnglish
Pages (from-to)68-73
Number of pages6
JournalPharmacogenetics and Genomics
DOIs
StateAccepted/In press - 2021
Externally publishedYes

Keywords

  • NAT2 genotype
  • adverse drug reactions
  • isoniazid monotherapy
  • pharmacogenomics

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