Anthropometric and Genetic Factors Associated With the Exposure of Rifampicin and Isoniazid in Mexican Patients With Tuberculosis

Abstract

Background: Tuberculosis (TB) remains a critical infectious, contagious disease worldwide with high prevalence and mortality rate. The directly observed treatment short-course therapy includes rifampicin (RMP) and isoniazid (INH) for at least 6 months. The purposes of this scheme are to interrupt the transmissibility of the Mycobacterium tuberculosis complex and to avoid secondary complications. Low plasma concentrations of these anti-TB drugs have been associated with extended treatment duration, therapeutic failure, and relapse. The determination of anthropometric, genetic, and clinical variables that may affect plasma concentrations of RMP and INH might facilitate the detection of patients at increased risk of therapeutic failure. Methods: A prospective observational study was performed in patients with TB diagnosis. A fixed-dose combined formulation was administered following clinical guidelines, and 12 venous blood samples were collected within 24 hours after dose for the quantification of plasma levels of RMP and INH by high-performance liquid chromatography-ultraviolet. The plasma concentrations versus time for each drug in each patient were assessed by a noncompartmental approach to obtain Cmax, and the area under the concentration–time curve to the last observation point (AUC0–24 h) was calculated by the linear trapezoidal rule. Genetic polymorphisms of the enzyme involved in INH metabolism (NAT2) and proteins involved in RMP transport (glycoprotein‐P and OATP1B1) were determined. Results: A total of 34 patients aged between 18 and 72 years with the diagnosis of TB were included in the current study. A multivariate analysis was performed to determine the anthropometric and genetic characteristics that modified the Cmax and AUC0–24 h of RMP and INH. Results indicated that RMP Cmax and AUC0–24 h were affected by sex, dose/weight, and single nucleotide polymorphism of MDR1. In addition, age, body mass index, and NAT2 acetylator genotype were shown to determine the Cmax and AUC0–24 h for INH. Conclusions: Anthropometric, genetic, and dosage characteristics of Mexican patients with TB are an important source of risk for subtherapeutic plasma concentrations of anti-TB drugs. Factors such as lower-than-recommended RMP dose, male patients with TB, and MDR1 3435 genotype, in addition to age group, body mass index, and INH acetylator phenotype based on NAT2 genotype, should be considered during treatment.

Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review

“…Three studies assessed the effect of four ABCB1 , rs1045642 rs2032582, rs1128503, and rs3842 ( ABCB1c.4036A>G ) SNPs. Huerta-García et al demonstrated that the rs1045642 TT genotype is a predictor that explains 34.8% of the variability in rifampicin Cmax and 48.5% of the variability in AUC0–24 h. 39 However, the other two studies did not replicate this observed result of Huerta-García et al 38 , 40 …”

“…There was variation among studies in sample size, the type of study participants, and the pharmacokinetics parameter compared with gene polymorphism. The smallest sample size was 34, 39 while the largest was 256. 34 The study participants were TB patients from 13 different countries and races.…”

“…However, the observed increase in AUC was not statistically significant. 39 A summary of specific transporters influence on pharmacokinetics is presented in Table 1 .…”

“…Huerta-García et al reported the AG genotype derived from SNP SLCO1B1 c.388A>G was associated with lower rifampicin AUC0–24 h values compared to those with AA genotype. 39 In post hoc analysis, Dompreh et al observed that the SLCO1B1 c.388AA genotype was associated with low rifampin concentrations compared to those with c.388GG . 42 The five remaining studies did not report any association between rs2306283 SNP and rifamycin pharmacokinetics.…”

“…The consequence of this change on the transporter function is not well elucidated. The patients who were homozygous wild type (AA) 42 and heterozygous (AG) 39 were reported to have lower rifampicin exposure. Similarly, no myopathy was observed with rs2306283 polymorphism which was observed in other SLCO1B1 genes in patients taking statins suggesting no effect or increased activity of the mutant variant.…”