Another Piece of the Puzzle for More Accurate Dosing of Clotting Factors in von Willebrand Disease

Dosing Concentrates in vWD

Perioperative administration of concentrates containing both von Willebrand factor (vWF) and factor VIII (FVIII) in patients with vWD has historically been based on the measurement of plasma FVIII concentrations, which is more accessible and was previously considered more significant. However, it is now recommended to also measure the activity of vWF during the first 36 postoperative hours, as vWF is crucial for primary hemostasis and wound closure. Significant interindividual variability in the pharmacokinetics of vWF/FVIII concentrates often results in plasma concentrations outside the desired therapeutic range during perioperative administration, increasing the risk of bleeding and thrombotic complications.

For these cases, a deeper study of drug pharmacokinetics using population pharmacokinetic methods is appropriate. These analyses result in mathematical models that help refine dosing and identify factors that significantly influence pharmacokinetics. Such models are also known from the treatment of hemophilia A and B. Dutch hematologists have developed a population pharmacokinetic model of plasma FVIII concentrations to individualize perioperative dosing of vWF/FVIII concentrate in patients with vWD.

Patient Population and Developed Model

Data for model creation were obtained from a retrospective cohort study, including patients with vWD undergoing surgery at several Dutch hemophilia treatment centers between 2000 and 2018. The model was developed using 684 FVIII measurements from 97 patients who underwent a total of 141 surgeries. Subsequently, the model was externally validated using 20 additional patients from one center who underwent 31 surgeries and provided 208 FVIII values. No thrombotic events developed in the patients; clinically significant bleeding was reported in 5 surgical procedures.

The pharmacokinetics of FVIII were best described by a linear one-compartment model. The created model, after adjustment for covariates and subsequent validation, demonstrated the absence of bias and adequate accuracy in estimating FVIII plasma concentration. Typical values for the distribution volume were 3.28 l/70 kg and for clearance 0.037 l/hr/70 kg. Increased vWF activity, higher surgical risk according to ASA (American Society of Anesthesiologists), and prolonged surgery duration were associated with reduced FVIII clearance.

Conclusion

Population pharmacokinetic modeling based on real-world data analyzed FVIII levels during the perioperative period when administering vWF/FVIII concentrate and identified factors influencing FVIII clearance. The model can help refine dosing in patients with vWD undergoing surgery and ensure safer surgical procedures while considering the individual variability in pharmacokinetic profiles among different patients.

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Source: de Jager N. C. B., Bukkems L. H., Heijdra J. M. et al. One piece of the puzzle: population pharmacokinetics of FVIII during perioperative Haemate P^®/Humate P^® treatment in von Willebrand disease patients. J Thromb Haemost 2020 Feb; 18 (2): 295–305, doi: 10.1111/jth.14652.