Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.
Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.
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DOI：
10.1128/aac.00210-17
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发表时间：
2017-07
影响因子：
4.9
通讯作者：
Davies GR
中科院分区：
文献类型：
--
作者：
Sloan DJ;McCallum AD;Schipani A;Egan D;Mwandumba HC;Ward SA;Waterhouse D;Banda G;Allain TJ;Owen A;Khoo SH;Davies GR
部分由遗传因素驱动的抗结核（TB）药物暴露的变化可能与不良临床结局相关。先前的研究表明SLCO 1B 1位点对利福平的血浆浓度-时间曲线下面积（AUC）有影响。我们评估了SLCO 1B 1和其他候选基因（AADAC和CES-1）的单核苷酸多态性（SNP）对马拉维个体间药代动力学变异性的贡献。共174例肺结核成人患者在给药后2 h和6 h进行了血浆利福平浓度采样。来自同一背景的47例集中采样的相似患者的既往队列数据可用于支持NONMEM v7.2中的群体药代动力学模型开发，使用两阶段策略改善吸收阶段的信息。与最近在南非和乌干达进行的研究相反，SLCO 1B 1中的SNP不能解释利福平AUC 0-∞的变异性。未发现与AADAC或CES-1 SNP的药代动力学相关性，这在马拉维人群中很少见。利福平暴露的药物遗传学决定因素在非洲人群中可能存在差异。SLCO 1B 1和其他新的候选基因，以及个体间变异的非遗传来源，应进一步探讨在地理上不同的，足够的权力队列。
Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0–∞ of rifampin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.