Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis

Abstract

Background: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered.

Objectives: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated.

Methods: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575.

Results: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10).

Conclusions: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups.

Figure 1.

Rifapentine AUC_0–24 versus AADAC rs1803155 genotypes. The median for each genotype is denoted by a line within the box that is bounded by first and third quartiles. Race: black, solid circles; non-black, open circles. (a) Unadjusted rifapentine AUC_0–24 for black and non-black participants. (b) Residual expressed as a percent of observed rifapentine AUC_0–24 relative to predicted AUC_0–24 that was adjusted for drug dose, food, sex and HIV coinfection for black participants. As none of the 43 non-black participants was coinfected with HIV, predicted AUC_0–24 in non-black participants was adjusted for drug dose, food and sex. Relative residuals were computed on the natural logarithm scale and converted by exponentiation.