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

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, 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 factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.

Fig. 1

Schematic workflow of predictive performance of population pharmacokinetic–pharmacodynamic models. CSA chromogenic substrate assay, OSA one-stage assay

Fig. 2

Correlations of factor VIII activity level with thrombin generation parameters. A Correlation between factor VIII activity level determined with the one-stage assay and chromogenic assay. Correlation of factor VIII activity level with B thrombin peak height, C thrombin potential, and D velocity of thrombin generation

Fig. 3

Factor VIII activity level, thrombin peak height, thrombin potential, and plasmin peak height after a bolus of factor VIII replacement therapy. A Factor VIII activity level measured with the one-stage assay, B thrombin peak height, C thrombin potential, and D plasmin peak height after a standardized bolus of plasma derived von Willebrand factor/factor VIII concentrate. Box represents median with interquartile range, whiskers indicate minimum and maximum, and dots are outliers. Dotted line represents mean of individual healthy control Nijmegen hemostasis assay measurements, gray area ± 2 standard deviations

Fig. 4

Factor VIII activity level and normalized thrombin peak height and thrombin potential after a bolus of factor VIII replacement therapy. Factor VIII activity level measured with the one-stage assay (in IU/dl on left y-axis, in black) and A thrombin peak height [as percentage of normal pooled plasma (NPP)] and B thrombin potential (as percentage of NPP), both on right y-axis in red, before and after a standardized bolus of plasma derived von Willebrand factor/factor VIII concentrate. The dots represent the median with the interquartile range

Fig. 5

Box plots of the prediction error (PE%) of the novel models vs Bukkems et al. Blue box plots indicate the PE of the models by Bukkems et al., and red box plots indicate the PE of the novel models, in which the pharmacokinetic or pharmacodynamic parameters are re-estimated. Within each box plot, horizontal black lines denote median values. Box plots extend from the first to the third quartile from each model. Black solid and dashed lines are reference lines indicating PE% of 0% or ± 20%, respectively

Fig. 6

Three patients from the external dataset with a similar pharmacokinetic profile displaying a different normalized thrombin potential response after factor VIII administration using the model by Bukkems et al. [16] The green lines display the individual prediction, the blue lines display the population prediction, and the red dots display the observed data