One piece of the puzzle: Population pharmacokinetics of FVIII during perioperative Haemate P®/Humate P® treatment in von Willebrand disease patients

Abstract

Introduction Many patients with von Willebrand disease (VWD) are treated on demand with von Willebrand factor and factor VIII (FVIII) containing concentrates present with VWF and/or FVIII plasma levels outside set target levels. This carries a risk for bleeding and potentially for thrombosis. Development of a population pharmacokinetic (PK) model based on FVIII levels is a first step to more accurate on‐demand perioperative dosing of this concentrate. Methods Patients with VWD undergoing surgery in Academic Haemophilia Treatment Centers in the Netherlands between 2000 and 2018 treated with a FVIII/VWF plasma‐derived concentrate (Haemate® P/Humate P®) were included in this study. Population PK modeling was based on measured FVIII levels using nonlinear mixed‐effects modeling (NONMEM). Results The population PK model was developed using 684 plasma FVIII measurements of 97 VWD patients undergoing 141 surgeries. Subsequently, the model was externally validated and reestimated with independent clinical data from 20 additional patients undergoing 31 surgeries and 208 plasma measurements of FVIII. The observed PK profiles were best described using a one‐compartment model. Typical values for volume of distribution and clearance were 3.28 L/70 kg and 0.037 L/h/70 kg. Increased VWF activity, decreased physical status according to American Society of Anesthesiologists (ASA) classification (ASA class >2), and increased duration of surgery were associated with decreased FVIII clearance. Conclusion This population PK model derived from real world data adequately describes FVIII levels following perioperative administration of the FVIII/VWF plasma‐derived concentrate (Haemate® P/Humate P®) and will help to facilitate future dosing in VWD patients.

Is pharmacokinetic-guided dosing of desmopressin and von Willebrand factor-containing concentrates in individuals with von Willebrand disease or low von Willebrand factor reliable and feasible? A protocol for a multicentre, non-randomised, open label cohort trial, the OPTI-CLOT: to WiN study

“…Population PK models for desmopressin and different VWF-containing concentrates have been constructed using NONMEM software (however not all of our models have been published yet) 9 10. These models are able to predict average PK parameters for VWF:Act and FVIII (as well as the interindividual variability of these PK parameters, and intraindividual variability of some of the PK parameters), in a population of individuals with VWD and low VWF.…”

“… 6–8 Population PK models that describe plasma VWF:Act and FVIII after administration of desmopressin or VWF-containing concentrates have been constructed by our group (however not all models have been published yet). 9 10 These models are based on retrospective DDAVP-testing data and VWF-containing concentrate treatment data from multiple haemophilia treatment centres in the Netherlands and in the UK. In a population PK model, the typical PK parameters and their corresponding variability are estimated.…”

“…However, pharmacokinetics (PK) of desmopressin and VWF-containing concentrates differ within and between patients (ie, intraindividual and interindividual differences), and large interindividual differences in response to desmopressin are observed 6–8. Population PK models that describe plasma VWF:Act and FVIII after administration of desmopressin or VWF-containing concentrates have been constructed by our group (however not all models have been published yet) 9 10. These models are based on retrospective DDAVP-testing data and VWF-containing concentrate treatment data from multiple haemophilia treatment centres in the Netherlands and in the UK.…”

Perioperative management for patients with von Willebrand disease: Defining the optimal approach

“…The complex variation between available VWD concentrates, VWD disease severity and the difference in VWF and/or FVIII levels after concentrate replacement makes population PK and personalised care more difficult to develop in patients with VWD, and some believe the use of population PK assessments to predict factor levels during surgery may not be reliable, due to the variability of individual PK parameters such as in vivo recovery values 40 . A recent study developed a population PK model to predict FVIII levels over time after administration of a plasma‐derived VWF/FVIII concentrate (Haemate ® P) to 97 patients 41 . This model was successfully used to monitor FVIII levels and could prove beneficial for tailoring treatment using PK‐guided dosing with this product 41 .…”

“…A recent study developed a population PK model to predict FVIII levels over time after administration of a plasma‐derived VWF/FVIII concentrate (Haemate ® P) to 97 patients 41 . This model was successfully used to monitor FVIII levels and could prove beneficial for tailoring treatment using PK‐guided dosing with this product 41 . However, using the patient's preoperative PK values, along with regular VWF/FVIII assessments as part of a comprehensive treatment plan throughout the perioperative period, is essential to predict post‐infusion circulating levels of VWF and FVIII required to achieve haemostasis.…”