TY - JOUR
T1 - Combining factor VIII levels and thrombin/plasmin generation
T2 - A population pharmacokinetic-pharmacodynamic model for patients with haemophilia A
AU - Bukkems, Laura H.
AU - Valke, Lars L. F. G.
AU - Barteling, Wideke
AU - Laros-van Gorkom, Britta A. P.
AU - Blijlevens, Nicole M. A.
AU - Cnossen, Marjon H.
AU - van Heerde, Waander L.
AU - Schols, Saskia E. M.
AU - Mathôt, Ron A. A.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85122721474&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34921439
U2 - https://doi.org/10.1111/bcp.15185
DO - https://doi.org/10.1111/bcp.15185
M3 - Article
C2 - 34921439
SN - 0306-5251
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
ER -