Population Pharmacokinetics of Perioperative Administration of Coagulation Factors in Patients with von Willebrand Disease
For many patients with von Willebrand disease, the administration of coagulation factors is an important part of perioperative care. Due to the absence of pharmacokinetic models, predicting therapeutic levels is challenging, leading to a higher risk of bleeding or thrombotic events. To create the missing model, a long-term study was conducted by Dutch authors.
Introduction
Current therapy for von Willebrand disease (VWD) focuses on normalizing the levels of von Willebrand factor (VWF) and coagulation factor VIII (FVIII) in cases of acute bleeding, post-operative situations, or trauma. Commonly used plasma derivatives containing VWF and FVIII include Haemate P®/Humate P®. Several studies, however, have observed inter-individual variability in the administration for acute bleeding or surgical procedures, likely caused by endogenous and exogenous factors.
The challenging prediction of therapeutic levels when administering concentrates can lead to bleeding or thrombotic complications. The goal of the study published by Dutch scientists was to create a population pharmacokinetic model that would provide a starting point for individualizing replacement therapy in perioperative care for patients with von Willebrand disease.
Methods and Study Course
The study included 97 patients who underwent a total of 141 surgical procedures between 2000 and 2018. The majority of subjects in the sample had type 1, 2A, and 2M VWD. They were administered Haemate P® in the perioperative period. For the purposes of developing the pharmacokinetic model, 684 plasma concentration measurements of coagulation factor VIII were performed. External validation was conducted using 208 coagulation factor VIII values in another 20 patients.
Most samples were collected over 168 hours from the time of surgery, with a median number of sample collections per hospitalization being 5. No thrombotic events were observed in the sample, and clinically relevant bleeding was reported in 5 surgical procedures.
Findings and Discussion
The pharmacokinetic model estimated typical values for distribution and clearance to be 3.28 L/70 kg and 0.037 L/h/70 kg. The lengthening of surgical time led to a decrease in FVIII clearance. Patients with ASA III and IV surgical risk had lower FVIII clearance compared to those with ASA II, supporting earlier findings that patients with comorbidities exhibit higher VWF and FVIII values.
Type of von Willebrand disease also significantly influenced pharmacokinetic parameters. Patients with types 2 and 3 had 54% and 74% higher clearance, respectively, compared to type 1 VWD patients. Given the sample composition, it is anticipated that the model will be less applicable to less common disease types (types 2B, 2N, and 3 collectively had only 8 participants). Another study limitation is the inability to distinguish between endogenous and exogenous FVIII.
Conclusion
The published study, despite certain limitations, creates a pharmacokinetic model describing FVIII levels in patients with von Willebrand disease during perioperative replacement therapy. This pharmacokinetic model will facilitate future estimates of replacement therapy dosing.
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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; 18 (2): 295–305, doi: 10.1111/jth.14652.
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