Quantification of the relationship between desmopressin concentration and Von Willebrand factor in Von Willebrand disease type 1: A pharmacodynamic study

Jessica M. Heijdra, Michael E. Cloesmeijer, for the OPTI-CLOT/ To WiN study group and SYMPHONY consortium, Nico C.B. de Jager, Frank W.G. Leebeek, Marieke H.J.A. Kruip, Marjon H. Cnossen, Ron A.A. Mathôt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Introduction: Desmopressin can be used to prevent bleeding in von Willebrand disease (VWD), but the relationship between desmopressin and von Willebrand factor activity (VWF:Act) has yet to be quantified. Aim: To quantify the relationship between desmopressin dose, its plasma concentration and the VWF:Act response in type 1 VWD patients. Methods: Forty-seven VWD patients (median age 25 years, IQR: 19–37; median body weight 71 kg, IQR: 59–86) received an IV desmopressin dose of.3 mcg/kg. In total, 177 blood samples were available for analysis. We developed an integrated population pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed effect modelling. Subsequently, we performed Monte Carlo simulations to investigate the efficacy of the current dosing regimen. Results: A one-compartment PK model best described the time profile of the desmopressin concentrations. 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. Typically, VWF:Act increased 452% with an EC50 of.174 ng/ml. Simulations demonstrated that after.3 mcg/kg desmopressin intravenously, >90% patients with a VWF:Act baseline of ≥.20 IU/mL attain a VWF:Act >.5 IU/ml up to ≥4 h after administration. A capped dose of 30 mcg was sufficient in patients weighing over 100 kg. Conclusion: The relationship between desmopressin and VWF:Act was quantified in a PK-PD model. The simulations provide evidence that recently published international guidelines advising an intravenous desmopressin dose of.3 mcg/kg with a capped dose of 30 mcg > 100 kg gives a sufficient desmopressin response.

Original languageEnglish
Pages (from-to)814-821
Number of pages8
JournalHaemophilia
Volume28
Issue number5
Early online date8 May 2022
DOIs
Publication statusPublished - Sept 2022

Bibliographical note

Funding Information:
J.M.H. has received an award from CSL Behring, outside the submitted work. F.W.G.L. has received unrestricted research grants from CSL Behring, Takeda, Sobi and uniQure, and is a consultant for Takeda, uniQure, and Biomarin of which fees go to the institution. He received travel support from Sobi. He is a DSMB member for a study sponsored by Roche. OPTI‐CLOT member M.J.H.A.K. has received grants from governmental research institutes such as ZonMW, Innovation Fund, as well as institutional grants, and has received unrestricted research grants from Sobi, outside the submitted work. She has received speaker's fee from Roche, Bristol Myers Squibb and Sobi that goes to the institution. R.A.A.M. has received travel grants from Shire and Bayer. M.H.C. has received grants from governmental research institutes such as NWO, ZonMW, and Innovation Fund, and institutional grants and unrestricted investigator research grants/educational and travel funding from the following companies over the years: Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a member on steering boards of Roche and Bayer. All grants, awards, and fees have gone to the institution. The remaining authors declare no competing financial interests. All unrestricted research grants, awards, educational grants, and consultancy fees have been forwarded to the respective institutions.

Funding Information:
MC is funded by The SYMPHONY consortium. The SYMPHONY consortium which aims to orchestrate personalized treatment in patients with bleeding disorders, is a unique collaboration between patients, health care professionals and translational & fundamental researchers specialized in inherited bleeding disorders, as well as experts from multiple disciplines. It aims to identify best treatment choice for each individual based on bleeding phenotype. In order to achieve this goal, work packages (WP) have been organized according to three themes for example Diagnostics (WPs 3 and 4); Treatment (WPs 5–9) and Fundamental Research (WPs 10–12). This research received funding from the Netherlands Organization for Scientific Research (NWO) in the framework of the NWA-ORC Call grant agreement NWA.1160.18.038. Principal investigator: Dr. M.H. Cnossen. Project manager: Dr. S.H. Reitsma. Beneficiaries of the SYMPHONY consortium: Erasmus MC and Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, project leadership and coordination; Sanquin Diagnostics; Sanquin Research; Amsterdam University Medical Centers; University Medical Center Groningen; University Medical Center Utrecht; Leiden University Medical Center; Radboud University Medical Center; Netherlands Society of Hemophilia Patients (NVHP); Netherlands Society for Thrombosis and Hemostasis (NVTH); Bayer B.V., CSL Behring B.V., Swedish Orphan Biovitrum (Belgium) BVBA/SPRL. This paper is written on behalf of the international multicentre “OPTI-CLOT” (patient tailOred PharmacokineTIc-guided dosing of CLOTting factor concentrates in bleeding disorders) and “To WiN” studies that aim to implement a PK-guided approach for the treatment of bleeding disorders using population PK models for desmopressin, factor concentrates and other alternative drugs. “OPTI-CLOT” and “To WiN” study group.

Funding Information:
MC is funded by The SYMPHONY consortium. The SYMPHONY consortium which aims to orchestrate personalized treatment in patients with bleeding disorders, is a unique collaboration between patients, health care professionals and translational & fundamental researchers specialized in inherited bleeding disorders, as well as experts from multiple disciplines. It aims to identify best treatment choice for each individual based on bleeding phenotype. In order to achieve this goal, work packages (WP) have been organized according to three themes for example Diagnostics (WPs 3 and 4); Treatment (WPs 5–9) and Fundamental Research (WPs 10–12). This research received funding from the Netherlands Organization for Scientific Research (NWO) in the framework of the NWA‐ORC Call grant agreement NWA.1160.18.038. Principal investigator: Dr. M.H. Cnossen. Project manager: Dr. S.H. Reitsma.

Publisher Copyright:
© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.

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