Download PDF
Thromb Haemost 2020; 120(10): 1407-1416
DOI: 10.1055/s-0040-1714349
Coagulation and Fibrinolysis

Population Pharmacokinetic Modeling of von Willebrand Factor Activity in von Willebrand Disease Patients after Desmopressin Administration

Nico C. B. de Jager    *
1   Hospital Pharmacy-Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
,
Jessica M. Heijdra   *
2   Department of Paediatric Haematology, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands
,
Quincy Kieboom
2   Department of Paediatric Haematology, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands
,
Marieke J. H. A. Kruip
3   Department of Haematology, Erasmus University Medical Centre, Rotterdam, The Netherlands
,
Frank W. G. Leebeek
3   Department of Haematology, Erasmus University Medical Centre, Rotterdam, The Netherlands
,
Marjon H. Cnossen   **
2   Department of Paediatric Haematology, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands
,
Ron A. A. Mathôt   **
1   Hospital Pharmacy-Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
,
for the OPTI-CLOT Group › Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Objective Most von Willebrand disease (VWD) patients can be treated with desmopressin during bleeding or surgery. Large interpatient variability is observed in von Willebrand factor (VWF) activity levels after desmopressin administration. The aim of this study was to develop a pharmacokinetic (PK) model to describe, quantify, and explain this variability.

Methods Patients with either VWD or low VWF, receiving an intravenous desmopressin test dose of 0.3 µg kg−1, were included. A PK model was derived on the basis of the individual time profiles of VWF activity. Since no VWF was administered, the VWF dose was arbitrarily set to unity. Interpatient variability in bioavailability (F), volume of distribution (V), and clearance (Cl) was estimated.

Results The PK model was developed using 951 VWF activity level measurements from 207 patients diagnosed with a VWD type. Median age was 28 years (range: 5–76), median predose VWF activity was 0.37 IU/mL (range: 0.06–1.13), and median VWF activity response at peak level was 0.64 IU/mL (range: 0.04–4.04). The observed PK profiles were best described using a one-compartment model with allometric scaling. While F increased with age, Cl was dependent on VWD type and sex. Inclusion resulted in a drop in interpatient variability in F and Cl of 81.7 to 60.5% and 92.8 to 76.5%, respectively.

Conclusion A PK model was developed, describing VWF activity versus time profile after desmopressin administration in patients with VWD or low VWF. Interpatient variability in response was quantified and partially explained. This model is a starting point toward more accurate prediction of desmopressin dosing effects in VWD.

Keywords

desmopressin response - empirical PK - von Willebrand disease

Authors' Contributions

N.d.J. wrote the manuscript. J.H. and Q.K. collected the clinical data. N.d.J. and R.M. performed the analyses and developed the empirical population PK model. M.C. supervised data collection. R.M. and M.C. jointly supervised this study, while F.L. and M.K. gave critical guidance. All authors contributed substantially to the critical revision of the manuscript, and approved the final draft.


* Both are first authors.


** Both are last authors.


† See [Supplementary Appendix A] for a full list of members of the study group.


Supplementary Material



Publication History

Received: 08 April 2020

Accepted: 05 June 2020

Article published online:
03 August 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Leebeek FWG, Eikenboom JCJ. Von Willebrand's disease. N Engl J Med 2016; 375 (21) 2067-2080
    CrossrefPubMedGoogle Scholar
  • 2 Roberts JC, Morateck PA, Christopherson PA. , et al; Zimmerman Program Investigators. Rapid discrimination of the phenotypic variants of von Willebrand disease. Blood 2016; 127 (20) 2472-2480
    CrossrefPubMedGoogle Scholar
  • 3 Matsui T, Hamako J. von Willebrand factor and von Willebrand disease. Rinsho Ketsueki 2016; 57 (10) 2113-2123
    PubMedGoogle Scholar
  • 4 Sadler JE, Budde U, Eikenboom JC. , et al; Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 4 (10) 2103-2114
    CrossrefPubMedGoogle Scholar
  • 5 Favaloro EJ, Pasalic L, Curnow J. Monitoring therapy during treatment of von Willebrand disease. Semin Thromb Hemost 2017; 43 (03) 338-354
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Gill JC, Castaman G, Windyga J. , et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood 2015; 126 (17) 2038-2046
    CrossrefPubMedGoogle Scholar
  • 7 Laffan MA, Lester W, O'Donnell JS. , et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (04) 453-465
    CrossrefPubMedGoogle Scholar
  • 8 Stoof SCM, Cnossen MH, de Maat MPM, Leebeek FWG, Kruip MJHA. Side effects of desmopressin in patients with bleeding disorders. Haemophilia 2016; 22 (01) 39-45
    CrossrefPubMedGoogle Scholar
  • 9 Nichols WL, Hultin MB, James AH. , et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14 (02) 171-232
    CrossrefPubMedGoogle Scholar
  • 10 Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977; 1 (8017): 869-872
    CrossrefPubMedGoogle Scholar
  • 11 Lethagen S, Harris AS, Sjörin E, Nilsson IM. Intranasal and intravenous administration of desmopressin: effect on F VIII/vWF, pharmacokinetics and reproducibility. Thromb Haemost 1987; 58 (04) 1033-1036
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 de la Fuente B, Kasper CK, Rickles FR, Hoyer LW. Response of patients with mild and moderate hemophilia A and von Willebrand's disease to treatment with desmopressin. Ann Intern Med 1985; 103 (01) 6-14
    CrossrefPubMedGoogle Scholar
  • 13 Mannucci PM, Vicente V, Alberca I. , et al. Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses. Thromb Haemost 1987; 58 (04) 1037-1039
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977; 1 (8017): 869-872
    CrossrefPubMedGoogle Scholar
  • 15 Hörl W. Other blood and immune disorders in chronic kidney disease. Comprhensive Clinical Nephrology 2010; 84: 959-968
    CrossrefPubMedGoogle Scholar
  • 16 Mannucci PM. Desmopressin: an historical introduction. Haemophilia 2008; 14 (Suppl. 01) 1-4
    CrossrefPubMedGoogle Scholar
  • 17 Heijdra JM, Cnossen MH, Leebeek FWG. Current and emerging options for the management of inherited von Willebrand disease. Drugs 2017; 77 (14) 1531-1547
    CrossrefPubMedGoogle Scholar
  • 18 Federici AB, Mazurier C, Berntorp E. , et al. Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study. Blood 2004; 103 (06) 2032-2038
    CrossrefPubMedGoogle Scholar
  • 19 Nederlandse Vereniging van Hemofiliebehandelaars (NVHB). Richtlijn: diagnostiek en behandeling van hemofilie en aanverwante hemostasestoornissen. Alphen aan den Rijn: Van Zuiden Commun BV. 2009
    PubMedGoogle Scholar
  • 20 Bodó I, Eikenboom J, Montgomery R. , et al. Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (07) 1345-1350
    CrossrefPubMedGoogle Scholar
  • 21 de Wee EM, Sanders YV, Mauser-Bunschoten EP. , et al; WiN study group. Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease. Thromb Haemost 2012; 108 (04) 683-692
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Atiq F, Meijer K, Eikenboom J. , et al; WiN study group. Comorbidities associated with higher von Willebrand factor (VWF) levels may explain the age-related increase of VWF in von Willebrand disease. Br J Haematol 2018; 182 (01) 93-105
    CrossrefPubMedGoogle Scholar
  • 23 Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed 2005; 79 (03) 241-257
    CrossrefPubMedGoogle Scholar
  • 24 Keizer RJ, van Benten M, Beijnen JH, Schellens JHM, Huitema ADR. Piraña and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Programs Biomed 2011; 101 (01) 72-79
    CrossrefPubMedGoogle Scholar
  • 25 Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)--a Perl module for NONMEM related programming. Comput Methods Programs Biomed 2004; 75 (02) 85-94
    CrossrefPubMedGoogle Scholar
  • 26 Preijers T, Hazendonk HCAM, Liesner R. , et al; OPTI-CLOT study group. Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery. J Thromb Haemost 2018; 16 (11) 2196-2207
    CrossrefPubMedGoogle Scholar
  • 27 Sanders YV, Giezenaar MA, Laros-van Gorkom BAP. , et al; WiN study group. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost 2014; 12 (07) 1066-1075
    CrossrefPubMedGoogle Scholar
  • 28 Lip GYH, Blann A. von Willebrand factor: a marker of endothelial dysfunction in vascular disorders?. Cardiovasc Res 1997; 34 (02) 255-265
    CrossrefPubMedGoogle Scholar
  • 29 Stachenfeld NS, Splenser AE, Calzone WL, Taylor MP, Keefe DL. Sex differences in osmotic regulation of AVP and renal sodium handling. J Appl Physiol (1985) 2001; 91 (04) 1893-1901
    CrossrefPubMedGoogle Scholar
  • 30 Flood VH. Perils, problems, and progress in laboratory diagnosis of von Willebrand disease. Semin Thromb Hemost 2014; 40 (01) 41-48
    PubMedGoogle Scholar
  • 31 Michelet R, Dossche L, Van Herzeele C, Van Bocxlaer J, Vermeulen A, Vande Walle J. ; SAFE-PEDRUG consortium. Claiming desmopressin therapeutic equivalence in children requires pediatric data: a population PKPD analysis. Eur J Clin Pharmacol 2018; 74 (03) 297-305
    CrossrefPubMedGoogle Scholar
  • 32 Chapin J. Von Willebrand disease in the elderly: clinical perspectives. Clin Interv Aging 2018; 13: 1531-1541
    CrossrefPubMedGoogle Scholar
  • 33 Rydz N, Grabell J, Lillicrap D, James PD. Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease. Haemophilia 2015; 21 (05) 636-641
    CrossrefPubMedGoogle Scholar
  • 34 Federici AB, Bucciarelli P, Castaman G. , et al. Management of inherited von Willebrand disease in Italy: results from the retrospective study on 1234 patients. Semin Thromb Hemost 2011; 37 (05) 511-521
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Ng C, Motto DG, Di Paola J. Diagnostic approach to von Willebrand disease. Blood 2015; 125 (13) 2029-2037
    CrossrefPubMedGoogle Scholar
  • 36 Lavin M, O'Donnell JS. How I treat low von Willebrand factor levels. Blood 2019; 133 (08) 795-804
    CrossrefPubMedGoogle Scholar
  • 37 Juul KV, Klein BM, Sandström R, Erichsen L, Nørgaard JP. Gender difference in antidiuretic response to desmopressin. Am J Physiol Renal Physiol 2011; 300 (05) F1116-F1122
    CrossrefPubMedGoogle Scholar
  • 38 Liu J, Sharma N, Zheng W. , et al. Sex differences in vasopressin V2 receptor expression and vasopressin-induced antidiuresis. Am J Physiol Renal Physiol 2011; 300 (02) F433-F440
    CrossrefPubMedGoogle Scholar
  • 39 Liu J, Ji H, Zheng W, Verbalis J, Sandberg K. Gonadal hormone regulation of the renal vasopressin V2 receptor. FASEB J 2008; 22 (01) 1159
    PubMedGoogle Scholar
  • 40 Sanders YV, van der Bom JG, Isaacs A. , et al; WiN Study Group. CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease. J Thromb Haemost 2015; 13 (06) 956-966
    CrossrefPubMedGoogle Scholar
  • 41 Smith NL, Chen MH, Dehghan A. , et al; Wellcome Trust Case Control Consortium. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121 (12) 1382-1392
    CrossrefPubMedGoogle Scholar
  • 42 Rydz N, Swystun LL, Notley C. , et al. The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels. Blood 2013; 121 (26) 5228-5237
    CrossrefPubMedGoogle Scholar