Background: Variability in the pharmacokinetics (PK) of first-line anti-tuberculosis drugs (rifampicin -RIF, isoniazid -INH and pyrazinamide (PZA)) is high and may be influenced by pharmacogenetic polymorphism. We performed a pharmacogenetic substudy in 90 participants with PK data from the HIRIF trial in Peru.
Methods: Relevant single nucleotide polymorphisms (SNPs) in the NAT2, SLCO1B1, AADAC and AOX1 locii were genotyped using real time PCR.
Results: The proportions of slow, intermediate and fast acetylators predicted by a conventional six-SNP NAT2 panel were 32.5%, 48.2% and 19.2% respectively. A single NAT2 tag SNP (rs1495741) agreed with the panel-predicted phenotype in 91% and was a better predictor of INH AUC. Accounting for discrepancies possibly caused by rare alleles not represented in the panel or that could be unequivocally resolved using observed AUC, sensitivity of the tag SNP was 97.7%. A previously described SNP in SLCO1B1 (rs4149032) was present at an allele frequency of 0.31 and appeared to influence RIF AUC and Cmax at a dose of 20 mg/kg, despite an extreme distribution of alleles across the randomised arms The AADAC SNP (rs1803155) predominated in the study population and was not linked to RIF PK, though an effect could have been missed due to sample size and allele frequency .There was no association between PZA PK and a common SNP in AOX1 (rs55754655).
Conclusions: A tag SNP approach may offer simpler and cheaper prediction of INH PK. Further exploration of the impact of SLCO1B1 SNPs on RIF PK is required in this and other populations.
Keywords: NAT2; SLCO1B1; isoniazid; pharmacogenetics; pharmacokinetics; rifampicin; tuberculosis.
© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America.