Effect of genetic variation of NAT2 on isoniazid, SLCO1B1, and CES2 on rifampin pharmacokinetics in Ghanaian children with tuberculosis [PublishAheadOfPrint]

Isoniazid and rifampin are essential components of first-line antituberculosis (anti-TB) therapy. Understanding the relationship between genetic factors and the pharmacokinetics of these drugs could be useful in optimizing treatment outcomes, but this is understudied in children. We investigated the relationship between N-acetyltransferase type 2 (NAT2) genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by SLCO1B1) and carboxylesterase 2 (CES2) single nucleotide polymorphisms (SNPs) and rifampin pharmacokinetics in Ghanaian children. Blood samples were collected at times 0, 1, 2, 4, and 8 hours post-dose in children with tuberculosis (TB) on standard first-line therapy for at least 4 weeks. Isoniazid and rifampin concentrations were determined by validated LC/MS/MS method and pharmacokinetic parameters calculated using noncompartmental analysis. Genotyping of NAT2, SLCO1B1 and CES2 SNPs were performed using validated TaqMan® genotyping assays. Kruskal—Wallis test was used to compare pharmacokinetic parameters among the three genotypic groups followed by Wilcoxon Rank Sum test for pairwise group comparisons. Genotype status inferred by the NAT2 4-SNP and 7-SNP genotyping panel identified children with slow acetylator phenotype but not the rapid. For rifampin, only the rare SLCO1B1*1b homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that NAT2 and SCLCO1B1*1b genotyping may have minimal clinical utility in dosing decisions at the population level in Ghanaian children, but it could be useful at the individual level or in populations that have high frequency of implicated genotypes. Further studies in other populations are warranted.

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