Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis

Pharmacogenomics. 2019 Mar;20(4):225-240. doi: 10.2217/pgs-2018-0166. Epub 2019 Feb 15.

Abstract

Aim: We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin.

Materials & methods: Genotypes for SLCO1B1, NAT2, PXR, ABCB1 and UGT1A genes were determined using a TaqMan® Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics.

Results: Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patients contributing drug concentrations, rapid and intermediate acetylators had 2.3- and 1.6-times faster isoniazid clearance than slow acetylators. No association was observed between rifampicin pharmacokinetics and SLCO1B1, ABCB1, UGT1A or PXR genotypes.

Conclusion: Clinical relevance of the effects of genetic variation on isoniazid concentrations and low first-line tuberculosis drug exposures observed require further investigation.

Trial registration: ClinicalTrials.gov NCT02114684.

Keywords: isoniazid; pharmacogenetics; pharmacokinetics; pyrazinamide; rifampicin; tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adult
  • Arylamine N-Acetyltransferase / genetics*
  • Female
  • Genotype
  • Glucuronosyltransferase / genetics
  • Humans
  • Isoniazid / administration & dosage
  • Isoniazid / pharmacokinetics*
  • Liver-Specific Organic Anion Transporter 1 / genetics
  • Male
  • Polymorphism, Single Nucleotide / genetics
  • Recurrence
  • Rifampin / administration & dosage
  • Rifampin / pharmacokinetics*
  • Tuberculosis / drug therapy*
  • Tuberculosis / genetics
  • Tuberculosis / pathology

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Liver-Specific Organic Anion Transporter 1
  • SLCO1B1 protein, human
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Isoniazid
  • Rifampin

Associated data

  • ClinicalTrials.gov/NCT02114684