A population approach of rifampicin pharmacogenetics and pharmacokinetics in Mexican patients with tuberculosis

• Published in: Tuberculosis (Edinburgh, Scotland) Scotland), 2020-09, Vol.124, p.101982, Article 101982
• Main Authors: Medellin-Garibay, Susanna Edith, Huerta-García, Ana Patricia, Rodríguez-Báez, Ana Socorro, Magaña-Aquino, Martín, Ortiz-Álvarez, Arturo, Portales-Pérez, Diana Patricia, Milán-Segovia, Rosa del Carmen, Romano-Moreno, Silvia
• Format: Article
• Language: English
• Subjects: Absorption; Anthropometry; Bioavailability; Body weight; Evaluation; Genetic diversity; Genetic variance; Information retrieval; Informed consent; Lag time; MDR1 protein; Medical records; Nucleotides; Patients; Pharmacogenetics; Pharmacokinetics; Pharmacology; Plasma; Population pharmacokinetics; Research ethics; Rifampicin; Rifampin; Single-nucleotide polymorphism; Therapeutic drug monitoring; Tuberculosis
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2020.101982

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. •Population pharmacokinetics of RMP that explores the influence of genetic covariates.•Initial RMP daily dose should be further stratified based on total body weight.•Bayesian estimation will allow therapeutic drug monitoring at early stages.