Population Pharmacokinetic Model in Patients with von Willebrand Disease

Introduction

von Willebrand disease (vWD) is the most common congenital hemorrhagic disorder, with an estimated prevalence between 0.6 and 1.3%. Patients with vWD can exhibit various bleeding tendencies related to quantitative or qualitative deficiencies of von Willebrand factor (vWF).

Treatment of vWD is usually episodic, during bleeding events or around the time of surgical procedures, when there is a need to temporarily normalize or nearly normalize the levels of vWF and coagulation factor VIII (FVIII). Therapeutic elevation of these factors can be achieved in mild forms of the disease through the administration of desmopressin; if ineffective or contraindicated, vWF/FVIII concentrate can be administered. Most plasma-derived concentrates contain both vWF and FVIII in varying ratios. Prolonged administration of these concentrates leads to the accumulation of FVIII, hypothetically raising the risk of a prothrombotic state.

Recently published studies have shown that patients with vWD receiving the vWF/FVIII concentrate HaemateP (vWF:FVIII ratio 2.4:1) may have measured levels of both factors outside the desired range. A potential solution might be the use of a pharmacokinetic (PK) model to help optimize dosing.

Development of a Population PK Model

Dutch experts developed an integrated population pharmacokinetic model that accounts for both vWF activity (vWF:Act) and FVIII. They used levels of vWF and FVIII from 118 patients aged 1 to 82 years, who underwent 174 surgeries and had 695 measured levels of vWF:Act and 894 levels of FVIII. Levels were measured following a perioperative administration schedule at various times. First, the population kinetics of individual factors were analyzed separately, and then their interaction (the effect of vWF on the clearance of FVIII) was incorporated into the calculations. The model also considered different analytical methods for determining vWF.

The average perioperative level of vWF:Act 1.23 IU/ml reduced FVIII clearance from 460 to 264 ml/h, extending the half-life of FVIII from 6.6 to 11.4 hours. In the presence of vWF, there was clearly reduced FVIII clearance, leading to an extended half-life. This finding confirms the observed higher FVIII levels in practice after repeated concentrate administration.

Clinical Application − Case Description

The authors also tested their model on a clinical case involving a 33-year-old patient with vWD and a planned ankle surgery. From 1 to 4 days before the procedure, the patient’s levels of vWF:Act and FVIII were measured a total of 4 times before and after administering the defined dose of concentrate. The surgery took place on the 6th day. Clinicians used a perioperative protocol for administering the concentrate according to guidelines, starting with 50 IU/kg initially and then 25 IU/kg every 12 hours. The patient’s measured levels of vWF:Act were lower than recommended by the guidelines for the first 2 days after surgery. The FVIII level was optimal but continued to rise during administration.

Researchers then used the preoperative data measured in this patient and proposed an individualized dosing regimen using the newly developed model. The calculated resulting levels of both factors were optimal throughout the monitored postoperative period, without FVIII accumulation.

Conclusion

According to the authors, the newly developed model adequately describes the pharmacokinetics of the interacting vWF:Act and FVIII. Clinical use of the model could aid in more precise dosing of the 2.4:1 ratio concentrate used in perioperative care for patients with von Willebrand disease. Utilizing the model could better achieve recommended levels of vWF:Act and FVIII, potentially improving the quality of life and cost-efficiency of treatment for these patients.

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Source: Bukkems L. H., Heijdra J. M., de Jager N. C. B. et al. Population pharmacokinetics of the von Willebrand factor–factor VIII interaction in patients with von Willebrand disease. Blood Adv 2021 Mar 9; 5 (5): 1513–1522, doi: 10.1182/bloodadvances.2020003891.