L.H. Bukkems (1), J.M. Heijdra (2), H.C.A.M. Hazendonk (2), N.C.B de Jager (1), C.J. Fijnvandraat (2), K. Meijer (4), F.W.G. Leebeek (5), M.H. Cnossen (2), R.A.A. Mathôt (1) for the “OPTI-CLOT” study group.
(1) Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, the Netherlands, (2) Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children’s Hospital Rotterdam, Rotterdam, the Netherlands, (3) Department of Pediatric Hematology, Amsterdam University Medical Centers, Amsterdam, the Netherlands, (4)Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, (5) Department of Hematology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
Objectives: Previous studies indicate that 65 to 91% of patients with von Willebrand Disease (VWD) treated with a von Willebrand Factor (VWF)/factor VIII (FVII) concentrate (ratio 2.4:1, Haemate® P/Humate P®) during surgery present with VWF and/or FVIII levels outside predetermined target levels.1 This can result in higher treatment costs and a hypothetical risk of thrombosis. Pharmacokinetic (PK)-guided dosing may resolve this problem. As several guidelines describe perioperative target levels for both FVIII and VWF to ensure hemostasis, application of an integrated population PK model describing FVIII as well as VWF activity (VWF:Act) levels may further optimize perioperative dosing and improve quality of care.2,3 In addition, a population PK model may also give insight into the mechanisms of FVIII accumulation observed in perioperative VWD patients treated with multiple VWF/FVIII concentrate doses.1,4
Methods: Patients with VWD undergoing surgery in one of five different hemophilia treatment centers in the Netherlands between 2000-2018 treated with Haemate P® were included in this study. The FVIII and VWF:Act levels were analyzed using nonlinear mixed-effect modelling software (NONMEM). The change in endogenous and exogenous FVIII and VWF:Act levels over time were described with two separate turnover models with a zero-order production rate kin and a 1st order elimination rate kout. These FVIII and VWF:Act models were then combined and the interaction between FVIII and VWF:Act was added. Since, VWF acts as a chaperone for FVIII protecting it from early proteolytic degradation and cellular uptake, the inhibitory effect of VWF on FVIII clearance was described with an Imax funtion.5
Monte Carlo simulations with 1,000 virtual patients of 70 kg were performed to evaluate the current Dutch treatment guidelines for perioperative patients with VWD. These virtual patients were dosed with a VWF/FVIII concentrate for a major surgery as described in the guideline.2 The achieved FVIII and VWF:Act levels were compared to the FVIII and VWF:Act target levels.
Results: The dataset consisted of 118 patients with different types of VWD (n type 1= 57; 2A = 32; 2B = 9; 2M = 11; 2N = 3; 3 = 6), aged 1 to 82 years, weighing 8.8 to 118 kg, undergoing 174 surgeries. Patients received a median of 5 doses (median bolus dose FVIII: 20.8 IU/kg) per surgery and a total of 894 FVIII and 695 VWF:Act levels were included. The structural model consisted of one compartment models for VWF:Act and FVIII. Typical values for VWF baseline, clearance and volume of distribution with corresponding interindividual variability values (IIV %) were 0.42 IU/mL (126.4%), 262 ml/h (55.3%) and 4990 ml (25.2%) for a patient of 70 kg, respectively. Typical values for FVIII clearance and volume of distribution were 460 ml/h (IIV: 81.5%) and 4350 ml, respectively. These values reflect the theoretical situation where VWF is not present. VWF inhibited FVIII clearance with an IC50 value of 1.65 IU/mL. Pre-dose (baseline) FVIII level was estimated on 0.77 IU/mL (IIV: 32.2%).
An average perioperative VWF:Act level of 1.23 IU/ml decreased the FVIII clearance from a typical value of 460 ml/h to 264 ml/h and increased FVIII elimination half-life from 6.6 to 11.4 hour. Clearly, when VWF was present the clearance of FVIII decreased and the half-life of FVIII increased, explaining the cumulative FVIII levels seen in the perioperative period after dosing with this concentrate.6
Monte Carlo simulations demonstrated that 100% and 87.1% of the patients did not drop below the minimal FVIII and VWF:Act target levels for a major surgery when the dosing recommendations are followed. However, high FVIII levels will be achieved, as for instance at 96h after start of the surgery the median patient will present with a FVIII level of 2.14 IU/mL (90% range: 1.10 – 4.02 IU/mL).
Conclusions:FVIII and VWF:Act levels after perioperative Haemate® P dosing were adequately described by this novel integrated population PK model. Application of this model could facilitate more accurate PK-guided perioperative dosing with this specific concentrate based on both FVIII and VWF:Act targets, potentially leading to improvement of quality and cost-effectiveness of care.
References:
[1] Hazendonk HCAM, Heijdra JM, de Jager NCB, et al. Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: Identifying the need for personalized treatment. Haemophilia 2018;24:460-470
[2] Nederlandse Vereniging van Hemofiliebehandelaars (NVHB). Richtlijn: Diagnostiek en behandeling van hemofilie en aanverwante hemostasestoornissen. 2009
[3] Connell NT, Flood VH, Brignardello-Petersen R, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021;5:301-325
[4] Gill JC, Shapiro A, Valentino LA, et al. von Willebrand factor/factor VIII concentrate (Humate-P) for management of elective surgery in adults and children with von Willebrand disease. Haemophilia 2011;17:895-905
[5] Miesbach W, Berntorp E. Interaction between VWF and FVIII in treating VWD. Eur J Haematol 2015;95:449-454
[6] Bukkems LH, Heijdra JM, de Jager NCB, et al. Population pharmacokinetics of the von Willebrand factor – factor VIII interaction in patients with von Willebrand disease. Blood Adv 2021;5:1513-1522
Reference: PAGE 29 (2021) Abstr 9722 [www.page-meeting.org/?abstract=9722]
Poster: Drug/Disease Modelling - Other Topics