Pharmacokinetic-Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate.

Autor: Valke LLFG; Department of Hematology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.; Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, The Netherlands., Cloesmeijer ME; Department of Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands., Mansouritorghabeh H; Clinical Research Development Unit, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran., Barteling W; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands., Blijlevens NMA; Department of Hematology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands., Cnossen MH; Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands., Mathôt RAA; Department of Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands., Schols SEM; Department of Hematology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.; Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, The Netherlands., van Heerde WL; Department of Hematology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. waander.vanheerde@radboudumc.nl.; Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, The Netherlands. waander.vanheerde@radboudumc.nl.; Enzyre BV, Novio Tech Campus, Nijmegen, The Netherlands. waander.vanheerde@radboudumc.nl.
Jazyk: angličtina
Zdroj: European journal of drug metabolism and pharmacokinetics [Eur J Drug Metab Pharmacokinet] 2024 Mar; Vol. 49 (2), pp. 191-205. Date of Electronic Publication: 2024 Feb 17.
DOI: 10.1007/s13318-024-00876-6
Abstrakt: Background: Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay.
Objective: The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic-pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters.
Methods: Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P ® ). The predictive performance of the previously developed pharmacokinetic-pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed.
Results: The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC 50 and E max values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%).
Conclusion: Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. The pharmacodynamic model is not factor specific and applicable to multiple factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.
(© 2024. The Author(s).)
Databáze: MEDLINE
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