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

Laura H. Bukkems, Lars L.F.G. Valke, Wideke Barteling, Britta A.P. Laros-van Gorkom, Nicole M.A. Blijlevens, Marjon H. Cnossen, Waander L. van Heerde, Saskia E.M. Schols, Ron A.A. Mathôt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 Emax functions. Results: The obtained EC50 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 EC50 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.

Original languageEnglish
Pages (from-to)2757-2768
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Issue number6
Early online date17 Dec 2021
Publication statusPublished - Jun 2022

Bibliographical note

Funding Information:
L.B. was funded by a grant from the Netherlands Organisation for Scientific Research (NWO) in the framework of the NWA‐ORC Call grant agreement NWA.1160.18.038. M.C. has received grants outside the submitted work from governmental research institutes such as NWO: ZonMW and NWO‐NWA and the Innovation fund, and unrestricted investigator‐initiated research grants as well as educational and travel funding from the following companies over the years: Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis and Nordic Pharma, and has served as a member on steering boards of Roche, Bayer and Octapharma. All grants, awards and fees are always collected by the institution. W.v.H. received unrestricted grants from Bayer, Shire, Novo Nordisk an CSL Behring. W.v.H. is the founder and CSO of Enzyre BV, a Radboudumc spinoff company. R.M. has received grants from governmental and societal research institutes such as NWO, ZonMW, Kidney Foundation and Innovation Fund and unrestricted investigator research grants from Baxter/Baxalta/Shire/Takeda, Bayer, CSL Behring, Sobi and CelltrionHC. He has served as advisor for Bayer, CSL Behring, Merck Sharp & Dohme, Baxter/Baxalta/Shire/Takeda. All grants and fees are paid to the institution. L.V., W.B., B.L.‐v.G., N.B. and S.S. have no conflict of interests to declare.

Publisher Copyright:
© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.


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