The aim of this study was to develop a population pharmacokinetic model of rifampicin (RMP) in Mexican patients with tuberculosis (TB) to evaluate the influence of anthropometric and clinical covariates, as well as genotypic variants associated with MDR1 and OATP1B1 transporters. A prospective study approved by Research Ethics Committee was performed at Hospital Central in San Luis Potosí, Mexico. TB patients under DOTS scheme and who signed informed consent were consecutively included. Anthropometric and clinical information was retrieved from medical records. Single nucleotide polymorphisms in MDR1 (C3435T) and SLCO1B1 (A388G and T521C) genes were evaluated. RMP plasma concentrations and time data were assessed with NONMEM software. A total of 71 Mexican TB patients from 18 to 72 years old were included for RMP quantification from 0.3 to 12 h after dose; 329 and 97 plasma concentrations were available for model development and validation, respectively. Sequential process includes a typical lag time of 0.25 h prior to absorption start with a Ka of 1.24 h-1 and a zero-order absorption of 0.62 h to characterize the gradual increase in RMP plasma concentrations. Final model includes total body weight in volume of distribution (0.7 L/kg, CV = 26.8%) and a total clearance of 5.96 L/h (CV = 38.5%). Bioavailability was modified according to time under treatment and generic formulation administration. In conclusion, a population pharmacokinetic model was developed to describe the variability in RMP plasma concentrations in Mexican TB patients. Genetic variants evaluated did not showed significant influence on pharmacokinetic parameters. Final model will allow therapeutic drug monitoring at early stages.

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墨西哥结核病患者中利福平药物遗传学和药代动力学的人群研究

本研究的目的是在墨西哥结核病 (TB) 患者中开发利福平 (RMP) 的群体药代动力学模型，以评估人体测量学和临床协变量的影响，以及与 MDR1 和 OATP1B1 转运蛋白相关的基因型变异。一项由研究伦理委员会批准的前瞻性研究在墨西哥圣路易斯波托西的中央医院进行。连续纳入DOTS计划下签署知情同意书的结核病患者。从医疗记录中检索人体测量学和临床信息。评估了 MDR1 (C3435T) 和 SLCO1B1 (A388G 和 T521C) 基因中的单核苷酸多态性。RMP 血浆浓度和时间数据用 NONMEM 软件评估。总共 71 名 18 至 72 岁的墨西哥结核病患者被纳入 RMP 量化，从 0 开始。给药后 3 至 12 小时；分别有 329 和 97 血浆浓度可用于模型开发和验证。顺序过程包括吸收开始前 0.25 小时的典型滞后时间，Ka 为 1.24 h-1，零级吸收为 0.62 小时，以表征 RMP 血浆浓度的逐渐增加。最终模型包括分布容积中的总体重 (0.7 L/kg, CV = 26.8%) 和 5.96 L/h (CV = 38.5%) 的总清除率。根据治疗时间和通用制剂给药修改生物利用度。总之，开发了一个群体药代动力学模型来描述墨西哥结核病患者中 RMP 血浆浓度的变异性。评估的遗传变异未显示对药代动力学参数的显着影响。