Michael E. Cloesmeijer(1)*, Jessica M. Heijdra(2)*, Nico C.B. de Jager(1), Frank W.G. Leebeek(3), Marieke H.J.A. Kruip(3), Marjon H. Cnossen**(2) and Ron A.A. Mathôt**(1) for the OPTI-CLOT/ To WiN study group
(1) Department of Hospital Pharmacy - Clinical Pharmacology, Amsterdam University Medical Center, Amsterdam, The Netherlands, (2) Department of Pediatric Hematology, Erasmus MC Sophia Children’s Hospital, University Medical Center Rotterdam, the Netherlands, (3) Department of Hematology, Erasmus MC, University Medical Center Rotterdam, the Netherlands. * Both are first authors; **Both are last authors
Introduction: Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by a deficiency or qualitative defect of von Willebrand factor (VWF)[1]. VWD is classified into three types, based on a partial or complete quantitative defect of VWF (type 1 and 3) or a qualitative defect of VWF (type 2)[2]. Type 2 is subdivided into subtypes 2A, 2B, 2M and 2N. In addition, individuals with VWF levels between 0.30-0.50 IU/mL are seen as a separate patient group (low VWF) [3].
Desmopressin is the treatment of choice for the prevention and treatment of bleeding in patients with type 1 VWD and low VWF, and in some patients with type 2A, 2M, and 2N VWD[4]. Desmopressin stimulates the release of endogenous VWF from vascular endothelial cells[5]. The maximum effect of desmopressin on the VWF:Actvity (VWF:Act) occurs approximately 1 hour after the start of administration[6]. Recently published international guidelines recommend an intravenous (IV) desmopressin dose of 0.3 mcg/kg, with a maximum (capped) dose of 20-30 mcg[7,8]. However, this recommendation is solely based on empirical evidence, and has not been supported by pharmacological evidence.
Objectives:
- Develop a population PK-PD model to quantify the concentration-effect relation of desmopressin on the VWF:Act response in VWD patients;
- Investigate the appropriateness of a capped desmopressin dose in VWD patients.
Methods: Fifty-four VWD patients (median age 25 years, range 8 – 70, median body weight 72 kg, range 35 – 123) received an IV desmopressin dose of 0.3 mcg/kg. In total, 205 blood samples were available for the assessment of desmopressin plasma concentrations and VWF:Act. We performed a sequential pharmacokinetic-pharmacodynamic (PK-PD) analysis method using nonlinear mixed effects modeling in NONMEM. First, we developed a PK model. The delayed VWF:Act response was modelled using a turnover model. With the PK-PD model, we performed Monte Carlo simulations to investigate the adequacy of the current dosing regimen. The VWF:Act response was considered effective when >90% of the simulated patients had VWF:Act levels greater than 0.50 IU/mL at 4 hours after desmopressin administration as stated in International VWD guidelines [9].
Results: The concentration-time data for desmopressin were adequately described using a one-compartment model. PK parameters were scaled allometricly. Females had a 27% higher volume of distribution compared to males. In the PD turnover model, the relationship between desmopressin plasma concentration and release of VWF:Act from the vascular endothelium was best described with an Emax model. Typical baseline release was increased 424% with an EC50 of 0.148 ng/mL. Simulations demonstrated that after 0.3 mcg/kg desmopressin, >90% patients with a VWF:Act baseline of 0.20 IU/mL attain a complete response (VWF:Act levels >0.50 IU/mL until at least 4 hours after administration). In all patients weighing >100 kg, a complete response was achieved after a capped dose of 30 mcg.
Conclusions: The relationship between desmopressin dose, desmopressin plasma concentration and VWF response was quantified in the developed PK-PD model. Simulations provide evidence that recently published international VWD guidelines on desmopressin dosing 0.30 mcg/kg with a capped dose of 30 mcg >100 kg lead to a clinically relevant desmopressin response.
References:
[1] Castaman G, Federici AB, Rodeghiero F, Mannucci PM. Von Willebrand’s disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment. Haematologica Italy; 2003; 88: 94–108.
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[6] Mannucci PM, Vicente V, Alberca I, Sacchi E, Longo G, Harris AS, Lindquist A. Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses. Thromb Haemost Germany; 1987; 58: 1037–9.
[7] Connell NT, Flood VH, Brignardello-Petersen R, Abdul-Kadir R, Arapshian A, Couper S, Grow JM, Kouides P, Laffan M, Lavin M, Leebeek FWG, O’Brien SH, Ozelo MC, Tosetto A, Weyand AC, James PD, Kalot MA, Husainat N, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021; 5: 301–25.
[8] Furqan F, Sham R, Kouides P. Efficacy and safety of half-dose desmopressin for bleeding prophylaxis in bleeding disorder patients undergoing predominantly low to moderate risk invasive procedures. Am J Hematol John Wiley & Sons, Ltd; 2020; 95: E285–7.
[9] Connell NT, Flood VH, Brignardello-Petersen R, Abdul-Kadir R, Arapshian A, Couper S, Grow JM, Kouides P, Laffan M, Lavin M, Leebeek FWG, O’Brien SH, Ozelo MC, Tosetto A, Weyand AC, James PD, Kalot MA, Husainat N, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021; 5: 301–25.
Reference: PAGE 29 (2021) Abstr 9846 [www.page-meeting.org/?abstract=9846]
Poster: Clinical Applications