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Population pharmacokinetics of isoniazid and dose recommendations in Mexican patients with tuberculosis

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Abstract

Background The standardized doses of isoniazid in therapy against tuberculosis are determined based on total body weight, without considering genetic polymorphisms of the metabolic enzyme N-acetyltransferase-2 that contribute to the wide pharmacokinetic variability of isoniazid. Objective The aim of this work was to build a population pharmacokinetic model of isoniazid in Mexican patients with tuberculosis to characterize typical estimates of pharmacokinetics, as well as inter-individual and residual variability of isoniazid considering the genetic factors associated with the N-acetyltransferase-2 enzyme. Setting A prospective study was conducted at the Department of Internal Medicine in Hospital Central, San Luis Potosí, México. Methods Plasma concentrations of isoniazid were measured by high performance liquid chromatography. The acetylator phenotype was predicted through single nucleotide polymorphisms in the N-acetyltransferase-2 gene. Genetic, anthropometric and clinical covariates were used to develop a pharmacokinetic model. Main outcome measure Isoniazid plasma concentration. Results A total of 69 patients with tuberculosis were included. Blood samples were drawn from 20 min to 12 h post dose to determinate the isoniazid plasma concentration. Typical pharmacokinetics parameters were characterized through two-compartment open model with first-order absorption and linear elimination. Clearance was different for each predicted N-acetyltransferase-2 phenotype being 11.4, 19.2 and 27.4 L/h for slow, intermediate and rapid acetylators, respectively. Central volume of distribution was determined as 1.5 * body mass index (L). Through the application of the model, external validation was performed and initial dose regimen of isoniazid is proposed based on stochastic simulations. Conclusion A validated population pharmacokinetic model of isoniazid was developed in Mexican patients with tuberculosis. Through the application of the final model, initial dose recommendations were provided considering body mass index and N-acetyltransferase-2 phenotype.

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Acknowledgements

The authors acknowledge the assistance of authorities and clinical staff of Coordinated Services of Health in San Luis Potosí and Hospital Central “Dr. Ignacio Morones Prieto”, San Luis Potosí, México; and the patients involved in this study.

Funding

This study was supported by Grants from CONACYT, Mexico Number FOMIX-CONACYT-SLP (FMSLP-2014-C02-250277); from FAI-UASLP (C15-FAI-04-67.67) to Milán-Segovia Rosa del Carmen, and from “Red Potosina Interinstitucional de Farmacogenética y Monitorización de Fármacos”. Huerta-Garcia Ana Patricia was the recipient of a scholarship (331463) from CONACYT. Medellín-Garibay Susanna E. was promoted for Retention at Universidad Autónoma de San Luis Potosí through Support Program for the incorporation of Scientists linked to the Institutional Consolidation of Research Groups and/or National Postgraduate Programs by CONACYT (Grant C-891/2018).

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Authors and Affiliations

  1. Faculty of Chemical Sciences, Universidad Autónoma de San Luis Potosí, Av. Manuel Nava #6, Zona Universitaria, C.P. 78210, San Luis Potosí, S.L.P., Mexico

    Ana Patricia Huerta-García, Susanna Edith Medellín-Garibay, Cristian Jazmín Rodríguez-Pinal, Diana Patricia Portales-Pérez, Silvia Romano-Moreno & Rosa del Carmen Milán-Segovia

  2. Department of Internal Medicine, Hospital Central “Dr. Ignacio Morones Prieto”, San Luis Potosí, S.L.P., Mexico

    Arturo Ortiz-Álvarez & Martín Magaña-Aquino

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  1. Ana Patricia Huerta-García
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  2. Susanna Edith Medellín-Garibay
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  4. Martín Magaña-Aquino
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  8. Rosa del Carmen Milán-Segovia
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Correspondence to Rosa del Carmen Milán-Segovia.

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Huerta-García, A., Medellín-Garibay, S., Ortiz-Álvarez, A. et al. Population pharmacokinetics of isoniazid and dose recommendations in Mexican patients with tuberculosis. Int J Clin Pharm 42, 1217–1226 (2020). https://doi.org/10.1007/s11096-020-01086-1

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