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

Authors: Valke, Lars L. F. G.; Cloesmeijer, Michael E.; Mansouritorghabeh, Hassan; Barteling, Wideke; Blijlevens, Nicole M. A.; Cnossen, Marjon H.; Mathot, Ron A. A.; Schols, Saskia E. M.; van Heerde, Waander L.

Affiliations: Radboud Univ Nijmegen, Dept Hematol, Med Ctr, POB 9101, NL-6500 HB Nijmegen, Netherlands. Hemophilia Treatment Ctr, Nijmege, Netherlands. Univ Amsterdam, Dept Hosp Pharm Clin Pharmacol, Locat AMC, Med Ctr, Amsterdam, Netherlands. Mashhad Univ Med Sci, Ghaem Hosp, Fac Med, Clin Res Dev Unit, Mashhad, Iran.

Publication: European Journal of Drug Metabolism and Pharmacokinetics. 2024

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 (R)). 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, EC50 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 factors concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.