Simulation of pharmacokinetic parameters of thiozonide in patients with low body weight based on a population pharmacokinetic model

Introduction. Patients diagnosed with pulmonary tuberculosis with multidrug-resistant or extensively drug-resistant pathogens (MDR-/XDR-TB) are characterized by reduced body weight (1, 2, 3). Under standard dosing regimens of antitubercular drugs, this can lead to altered pharmacokinetic parameters, increasing the risk of adverse reactions or reduced therapeutic efficacy. Therefore, mathematical modeling of the effect of body weight on the pharmacokinetics of the new domestic drug thiozonide is relevant for substantiating optimal dosing regimens.

Aim. To develop a mathematical model for assessing the influence of body weight on the pharmacokinetic parameters of thiozonide and to analyze the modeling results for individualized dosing approaches.

Materials and methods. The Julia programming environment and the Pumas.jl package were used for modeling. A two-compartment pharmacokinetic model with first-order kinetics and absorption, modified by the Weibull function, was developed. For each scenario, groups of patients with different fixed body weights (40, 50, 60, 70, and 80 kg) were considered, and 10 000 simulations were performed.

Results and discussion. Analysis of the simulation results showed that the maximum drug concentration (C_max) increased as body weight decreased; however, the maximum relative difference between the extreme groups (40 and 80 kg) was 17,08 %. Minimum concentrations (C_tau) remained stable across all groups, showing relative changes of less than 2,5 %. The area under the concentration-time curve (AUC_tau) varied from 2,88 to 7,23 %.

Conclusion. The study confirmed that there is no need to adjust the dosing regimen of thiozonide for patients weighing 40 to 80 kg.

1. LLerena A., Peñas-LLedó E., de Andrés F., Mata-Martín C., Sánchez C. L., Pijierro A., Cobaleda J. Clinical implementation of pharmacogenetics and personalized drug prescription based on e-health: the MedeA initiative. Drug Metabolism and Drug Interactions. 2020;35(3):20200143. DOI: 10.1515/dmpt-2020-0143.

2. Thu V. T. A., Dat L.D., Jayanti R. P., Trinh H. K. T., Hung T. M., Cho Y.-S., Long N. P., Shin J.-G. Advancing personalized medicine for tuberculosis through the application of immune profiling. Frontiers in Cellular and Infection Microbiology. 2023;13:1108155. DOI: 10.3389/fcimb.2023.1108155.

3. Cattermole G. N., Wells M. Comparison of adult weight estimation methods for use during emergency medical care. JACEP Open. 2021;2(4):e12515. DOI: 10.1002/emp2.12515.

4. Mamedsahatova S. Ch., Gurbanmyradova D. G. Hygienic assessment of nutritional status of patients with multidrug-resistant pulmonary tuberculosis. International Journal of Humanities and Natural Sciences. 2024;10–4(97):7–12. (In Russ.) DOI: 10.24412/2500-1000-2024-10-4-7-12.

5. Veselova E. I., Kuznetsova E. N., Peregudova A. B., Tinkova V. V., Kazyulina A. A., Vasilyeva I. A. Generalized Mycobacteriosis in HIV Patients. Tuberculosis and Lung Diseases. 2024;102(5):50–57. (In Russ.) DOI: 10.58838/2075-1230-2024-102-5-50-57.

6. Chiang C.-Y., Yu M.-C., Shih H.-C., Yen M.-Y., Hsu Y.-L., Yang S.-L., Lin T.-P., Bai K.-J. Improved consistency in dosing anti-tuberculosis drugs in Taipei, Taiwan. PLoS ONE. 2012;7(8):e44133. DOI: 10.1371/journal.pone.0044133.

7. Bezanson J., Edelman A., Karpinski S., Shah V. B. Julia: A fresh approach to numerical computing. SIAM Review. 2017;59(1):65–98. DOI: 10.1137/141000671.

8. Rackauckas C., Ma Y., Noack A., Dixit V., Mogensen P. K., Elrod C., Tarek M., Byrne S., Maddhashiya S., Santiago Calderón J. B. Nyberg J., Gobburu J. V. C., Ivaturi V. Accelerated predictive healthcare analytics with pumas, a high performance pharmaceutical modeling and simulation platform. BioRxiv. 2020;11. DOI: 10.1101/2020.11.28.402297.

9. Arnautov V. S. PharmCat/MetidaNCA.jl: (v0.7.1). Zenodo. 2025. DOI: 10.5281/zenodo.15793888.

10. Mason P. H., Degeling C., Denholm J. Sociocultural dimensions of tuberculosis: an overview of key concepts. The International Journal of Tuberculosis and Lung Disease. 2015;19(10):1135–1143. DOI: 10.5588/ijtld.15.0066.

11. Savchenko A. Y., Ramenskaya G. V., Bourenkov M. S. The safety and tolerability study of tiozonid in single dose with it increasing. Good Clinical Practice. 2016;3:43–48. (In Russ.)

12. Savchenko A. Yu., Menshikova L. A., Rameskaya G. V., Smolyarchuk E. A. Studying pharmacokinetics of new anti-tuberculosis drug thiozonide in blood plasma. Pharmaceutical Chemistry Journal. 2015;49(3):3–6.