Ahmed A Abulfathi1, Piyanan Assawasuwannakit2, Peter R Donald3, Andreas H Diacon4,5, Helmuth Reuter6, Elin M Svensson2,7. 1. Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. aaabulfathi@sun.ac.za. 2. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. 3. Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. 4. Task Applied Science, Bellville, South Africa. 5. Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. 6. Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. 7. Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
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.
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.
Authors: Anneke C Hesseling; Paolo Denti; Louvina E van der Laan; Anthony J Garcia-Prats; H Simon Schaaf; Maxwell Chirehwa; Jana L Winckler; Jun Mao; Heather R Draper; Lubbe Wiesner; Jennifer Norman; Helen McIlleron; Peter R Donald Journal: Antimicrob Agents Chemother Date: 2022-05-04 Impact factor: 5.938
Authors: Marieke G G Sturkenboom; Anne-Grete Märtson; Elin M Svensson; Derek J Sloan; Kelly E Dooley; Simone H J van den Elsen; Paolo Denti; Charles A Peloquin; Rob E Aarnoutse; Jan-Willem C Alffenaar Journal: Clin Pharmacokinet Date: 2021-03-06 Impact factor: 6.447