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

Overview

Journal Eur J Drug Metab Pharmacokinet

Date 2024 Feb 17

PMID 38367175

Authors

Lars L F G Valke

Michael E Cloesmeijer

Hassan Mansouritorghabeh

Wideke Barteling

Nicole M A Blijlevens

Marjon H Cnossen

Ron A A Mathot

Saskia E M Schols

Waander L van Heerde

Affiliations

Soon will be listed here.

Abstract

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 and E 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.

References

Takeyama M, Nogami K, Shima M . A new parameter in the thrombin generation assay, mean velocity to peak thrombin, reflects factor VIII activity in patients with haemophilia A. Haemophilia. 2016; 22(5):e474-7. DOI: 10.1111/hae.13052. View

Nguyen T, Mouksassi M, Holford N, Al-Huniti N, Freedman I, Hooker A . Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics. CPT Pharmacometrics Syst Pharmacol. 2016; 6(2):87-109. PMC: 5321813. DOI: 10.1002/psp4.12161. View

Bukkems L, Valke L, Barteling W, Laros-van Gorkom B, Blijlevens N, Cnossen M . Combining factor VIII levels and thrombin/plasmin generation: A population pharmacokinetic-pharmacodynamic model for patients with haemophilia A. Br J Clin Pharmacol. 2021; 88(6):2757-2768. PMC: 9304184. DOI: 10.1111/bcp.15185. View

Sheiner L, Beal S . Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm. 1981; 9(4):503-12. DOI: 10.1007/BF01060893. View

Valke L, Bukkems L, Barteling W, Laros-van Gorkom B, Blijlevens N, Mathot R . Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation. J Thromb Haemost. 2020; 18(12):3222-3231. PMC: 7756259. DOI: 10.1111/jth.15106. View

Oldenburg J . Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood. 2015; 125(13):2038-44. DOI: 10.1182/blood-2015-01-528414. View

Matsumoto T, Nogami K, Shima M . Simultaneous measurement of thrombin and plasmin generation to assess the interplay between coagulation and fibrinolysis. Thromb Haemost. 2013; 110(4):761-8. DOI: 10.1160/TH13-04-0345. View

Stemberger M, Kallenbach F, Schmit E, McEneny-King A, Germini F, Yeung C . Impact of Adopting Population Pharmacokinetics for Tailoring Prophylaxis in Haemophilia A Patients: A Historically Controlled Observational Study. Thromb Haemost. 2019; 119(3):368-376. DOI: 10.1055/s-0039-1677700. View

Ketteler C, Hoffmann I, Davidson S, Chen D, Tiede A, Richter N . Impact of different factor VIII inhibitor kinetic profiles on the inhibitor titer quantification using the modified Nijmegen-Bethesda assay. Res Pract Thromb Haemost. 2022; 6(8):e12799. PMC: 9743337. DOI: 10.1002/rth2.12799. View

10.

Simpson M, Goldenberg N, Jacobson L, Bombardier C, Hathaway W, Manco-Johnson M . Simultaneous thrombin and plasmin generation capacities in normal and abnormal states of coagulation and fibrinolysis in children and adults. Thromb Res. 2011; 127(4):317-23. DOI: 10.1016/j.thromres.2010.12.011. View

11.

Dargaud Y, Beguin S, Lienhart A, Al Dieri R, Trzeciak C, Bordet J . Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost. 2005; 93(3):475-80. DOI: 10.1160/TH04-10-0706. View

12.

Dargaud Y, Negrier C, Rusen L, Windyga J, Georgiev P, Bichler J . Individual thrombin generation and spontaneous bleeding rate during personalized prophylaxis with Nuwiq (human-cl rhFVIII) in previously treated patients with severe haemophilia A. Haemophilia. 2018; 24(4):619-627. DOI: 10.1111/hae.13493. View

13.

Verhagen M, Valke L, Schols S . Thrombin generation for monitoring hemostatic therapy in hemophilia A: A narrative review. J Thromb Haemost. 2022; 20(4):794-805. PMC: 9305107. DOI: 10.1111/jth.15640. View

14.

Mosnier L, Lisman T, van den Berg H, Nieuwenhuis H, Meijers J, Bouma B . The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration. Thromb Haemost. 2001; 86(4):1035-9. View

15.

Dardikh M, Albert T, Masereeuw R, Oldenburg J, Novakova I, van Heerde W . Low-titre inhibitors, undetectable by the Nijmegen assay, reduce factor VIII half-life after immune tolerance induction. J Thromb Haemost. 2012; 10(4):706-8. DOI: 10.1111/j.1538-7836.2012.04645.x. View

16.

Dargaud Y, Wolberg A, Gray E, Negrier C, Hemker H . Proposal for standardized preanalytical and analytical conditions for measuring thrombin generation in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost. 2017; 15(8):1704-1707. PMC: 5680042. DOI: 10.1111/jth.13743. View

17.

Zhou J, Barnes R, Foster G, Iorio A, Cramer T, von Drygalski A . Joint Bleeding Tendencies in Adult Patients With Hemophilia: It's Not All Pharmacokinetics. Clin Appl Thromb Hemost. 2019; 25:1076029619862052. PMC: 6714908. DOI: 10.1177/1076029619862052. View

18.

van Geffen M, Heerde W . Global haemostasis assays, from bench to bedside. Thromb Res. 2012; 129(6):681-7. DOI: 10.1016/j.thromres.2011.12.006. View

19.

Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe S . WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020; 26 Suppl 6:1-158. DOI: 10.1111/hae.14046. View

20.

Mannucci P, Tuddenham E . The hemophilias--from royal genes to gene therapy. N Engl J Med. 2001; 344(23):1773-9. DOI: 10.1056/NEJM200106073442307. View