Abstract
Purpose
Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8–12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure–response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens.
Methods
To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER.
Results
The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for ≥ 98% of the dosing interval in all the evaluated PASER regimens.
Conclusion
The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.
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Acknowledgments
We are grateful to Mats Karlsson and Lénaïg Tanneau for the initial analyses plan and to Bernd Rosenkranz and Sherwin Sy for providing the datasets.
Funding
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. AAA and EMS are supported by PanACEA, which is part of the European and Developing Countries Clinical Trials Partnership (EDCTP) 2 programme supported by the European Union (grant number TRIA2015–1102-PanACEA).
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AAA contributed in developing the research questions, data formatting, designing and execution of the modelling and simulation study, interpreting the results and drafting the manuscript. PA contributed in data formatting, designing of the modelling study and critical review of the manuscript. PRD, AHD and HR contributed in the conceptual design of the study, interpreting the results and critical review of the manuscript. EMS contributed in developing the research questions, designing and supervision of the modelling and simulation study, interpreting the results and critical review of the manuscript.
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Stellenbosch University’s Health Research Ethics Committee (S19/01/007) approved this study.
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Abulfathi, A.A., Assawasuwannakit, P., Donald, P.R. et al. Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens. Eur J Clin Pharmacol 76, 1557–1565 (2020). https://doi.org/10.1007/s00228-020-02943-8
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DOI: https://doi.org/10.1007/s00228-020-02943-8