Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens
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PHARMACOKINETICS AND DISPOSITION
Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens Ahmed A. Abulfathi 1 Elin M. Svensson 2,6
&
Piyanan Assawasuwannakit 2 & Peter R. Donald 3 & Andreas H. Diacon 4,5 & Helmuth Reuter 1 &
Received: 11 March 2020 / Accepted: 19 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Para-aminosalicylic acid . Tuberculosis . Pharmacokinetics . Modelling . PK/PD
Introduction Para-aminosalicylic acid (PAS) is one of the essential add-on Group C medicines recommended by the World Health Organization for the treatment of drug resistant tuberculosis
(TB) [1]. Early British Medical Research Council studies documented successful use of sodium PAS to treat pulmonary TB [2–5]. In addition, the combination of sodium PAS with streptomycin or isoniazid prevented resistance emergence in companion drugs [2–5]. Soon following PAS introduction to
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-02943-8) contains supplementary material, which is available to authorized users. * Ahmed A. Abulfathi [email protected] 1
2
Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Department of Pharmaceutical Biosc
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