Population pharmacokinetic modeling of factor concentrates in hemophilia: An overview and evaluation of best practice

the OPTI-CLOT study group, SYMPHONY consortium

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The accuracy of pharmacokinetic (PK)-guided dosing depends on the clinical and laboratory data used to construct a population PK model, as well as the patient’s individual PK profile. This review provides a detailed overview of data used for published population PK models for factor VIII (FVIII) and factor IX (FIX) concentrates, to support physicians in their choices of which model best suits each patient. Furthermore, to enhance detailed data collection and documentation, we do suggestions for best practice. A literature search was performed; publications describing prophylactic population PK models for FVIII and FIX concentrates based on original patient data and constructed using nonlinear mixed-effect modeling were included. The following data were collected: detailed demographics, type of product, assessed and included covariates, laboratory specifications, and validation of models. Included models were scored according to our recommendations for best practice, specifically scoring the quality of data documentation as reported. Respectively, 20 models for FVIII and 7 for FIX concentrates were retrieved. Although most models (22/27) included pediatric patients, only 4 reported detailed demographics. The wide range of body weights suggested that overweight and obese adults were represented. Twenty-six models reported the assay applied to measure factor levels, whereas only 16 models named reagents used. Eight models were internally validated using a data subset. This overview presents detailed information on clinical and laboratory data used for published population PK models. We provide recommendations on data collection and documentation to increase the reliability of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Original languageEnglish
Pages (from-to)4314-4325
Number of pages12
JournalBlood advances
Issue number20
Publication statusPublished - 26 Oct 2021

Bibliographical note

Funding Information:
Conflict-of-interest disclosure: M.H.C. has received grants from governmental and societal research institutes such as NWO, ZonMW, Innovation fund, from private funding institutions, institutional grants and unrestricted investigator research grants/ educational and travel funding from the following companies over

Funding Information:
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 and fundamental researchers specializing 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. To achieve this goal, work packages (WP) have been organized according to 3 themes (eg, 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: M.H. Cnossen; project manager: 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, Netherlands Society for Thrombosis and Hemostasis, Bayer B.V., CSL Behring B.V., and Swedish Orphan Biovitrum (Belgium) BVBA/SPRL. This study was also performed as part of the OPTI-CLOT international multicenter research consortium, “Patient Tailored Pharmacokinetic (PK) Guided Dosing of Clotting Factor Concentrates and Desmopressin in Bleeding Disorders,” which is currently WP 6 within the SYMPHONY consortium. This paper is written on behalf of the international multicenter OPTI-CLOT 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 members are: Steering committee: M.H. Cnossen (principal investigator and chair), F.W.G. Leebeek, Erasmus MC Sophia Children’s Hospital and Erasmus MC, University Medical Center Rotterdam, Rotterdam; R.A.A. Mathôt (co-leading investigator), K. Fijnvandraat, M. Coppens, Amsterdam University Medical Center, Amsterdam, University Medical Center, Amsterdam; K. Meijer, University Medical Center Groningen, Groningen; S.E.M. Schols, Radboud University Medical Centre, Nijmegen; H.C.J. Eikenboom, Leiden University Medical Centre, Leiden; R.E.G. Schutgens, University Medical Center Utrecht, Utrecht; E.A.M. Beckers, Maas-tricht University Medical Center, Maastricht; and P. Ypma, Haga Hospital, The Hague. Principal investigators and local collaborators in the Netherlands: M.J.H.A. Kruip, S. Polinder, Erasmus MC, University Medical Center Rotterdam, Rotterdam; R.Y.J. Tamminga, University Medical Centre Groningen, Gro-ningen; P. Brons, Radboud University Medical Centre, Nijmegen; K. Fischer, K.P.M. van Galen, University Medical Centre Utrecht, Utrecht; F.C.J.I. Heubel-Moenen, Maastricht University Medical Centre, Maastricht; L. Nieuwenhuizen, Maxima Medical Centre, Eindhoven; M.H.E. Driessens, The Netherlands Hemophilia Patient Society; I. van Vliet, Erasmus MC, University Medical Centre Rotterdam, Rotterdam. OPTI-CLOT/To WiNs: J. Lock, H.C.A.M. Hazendonk, I. van Moort, J.M. Heijdra, M..H.J. Goedhart, W. Al Arashi, Erasmus MC, University Medical Center Rotterdam, Rotterdam; T. Preijers, N.C.B. de Jager, L.H. Bukkems, M.E. Cloesmeijer, A. Janssen, Amsterdam University Medical Centers, Amsterdam. Principal investigators and local collaborators in the United Kingdom—P.W. Collins, Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff; R. Liesner, Great Ormond Street Haemophilia Centre, Great Ormond Street Hospital for Children NHS Trust, London; P. Chowdary, Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London; C.M. Millar, Hammersmith Hospital-Imperial College Healthcare NHS Trust, London; D. Hart,

Publisher Copyright:
© 2021 by The American Society of Hematology.


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