Combining factor VIII levels and thrombin/plasmin generation: A population pharmacokinetic-pharmacodynamic model for patients with haemophilia A.

Autor: Bukkems LH; Department of Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Valke LLFG; Department of Hematology, Radboud University Medical Centre, Nijmegen, The Netherlands.; Hemophilia Treatment Centre, Nijmegen Eindhoven Maastricht, The Netherlands., Barteling W; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Centre, Nijmegen, The Netherlands., Laros-van Gorkom BAP; Department of Hematology, Radboud University Medical Centre, Nijmegen, The Netherlands.; Hemophilia Treatment Centre, Nijmegen Eindhoven Maastricht, The Netherlands., Blijlevens NMA; Department of Hematology, Radboud University Medical Centre, Nijmegen, The Netherlands., Cnossen MH; Department of Pediatric Hematology, Erasmus MC - Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands., van Heerde WL; Hemophilia Treatment Centre, Nijmegen Eindhoven Maastricht, The Netherlands.; Enzyre BV, Novio Tech Campus, Nijmegen, The Netherlands., Schols SEM; Department of Hematology, Radboud University Medical Centre, Nijmegen, The Netherlands.; Hemophilia Treatment Centre, Nijmegen Eindhoven Maastricht, The Netherlands., Mathôt RAA; Department of Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2022 Jun; Vol. 88 (6), pp. 2757-2768. Date of Electronic Publication: 2022 Jan 15.
DOI: 10.1111/bcp.15185
Abstrakt: Aims: Prophylactic treatment of haemophilia A patients with factor VIII (FVIII) concentrate focuses on maintaining a minimal trough FVIII activity level to prevent bleeding. However, due to differences in bleeding tendency, the pharmacokinetic (PK)-guided dosing approach may be suboptimal. An alternative approach could be the addition of haemostatic pharmacodynamic (PD) parameters, reflecting a patient's unique haemostatic balance. Our aim was to develop a population PK/PD model, based on FVIII activity levels and Nijmegen Haemostasis Assay (NHA) patterns, a global haemostatic assay that measures thrombin/plasmin generation simultaneously.
Methods: PK/PD measurements were collected from 30 patients treated with standard half-life FVIII concentrate. The relationship between FVIII activity levels and the thrombin/plasmin generation parameters (thrombin potential, thrombin peak height and plasmin peak height), were described by sigmoidal E max functions.
Results: The obtained EC 50 value was smallest for the normalized thrombin potential (11.6 IU/dL), followed by normalized thrombin peak height (56.6 IU/dL) and normalized plasmin peak height (593 IU/dL), demonstrating that normalized thrombin potential showed 50% of the maximal effect at lower FVIII activity levels. Substantial inter-individual variability in the PD parameters, such as EC 50 of thrombin potential (86.9%) was observed, indicating that, despite similar FVIII activity levels, haemostatic capacity varies significantly between patients.
Conclusion: These data suggest that dosing based on patients' individual PK/PD parameters may be beneficial over dosing solely on individual PK parameters. This model could be used as proof-of-principle to examine the application of PK/PD-guided dosing. However, the relation between the PD parameters and bleeding has to be better defined.
(© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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