Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B

Tine M H J Goedhart; Laura H Bukkems; Anne-Fleur Zwagemaker; Michiel Coppens; Karin Fijnvandraat; Saskia E M Schols; Roger E G Schutgens; Jeroen Eikenboom; Floor C J I Heubel-Moenen; Paula F Ypma; Laurens Nieuwenhuizen; Karina Meijer; Frank W G Leebeek; Ron A A Mathôt; Marjon H Cnossen

doi:10.1016/j.rpth.2024.102397

Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B

Res Pract Thromb Haemost. 2024 Mar 28;8(3):102397. doi: 10.1016/j.rpth.2024.102397. eCollection 2024 Mar.

Authors

Tine M H J Goedhart¹, Laura H Bukkems², Anne-Fleur Zwagemaker³, Michiel Coppens^{4

5}, Karin Fijnvandraat³, Saskia E M Schols^{6

7}, Roger E G Schutgens⁸, Jeroen Eikenboom⁹, Floor C J I Heubel-Moenen¹⁰, Paula F Ypma¹¹, Laurens Nieuwenhuizen¹², Karina Meijer¹³, Frank W G Leebeek¹⁴, Ron A A Mathôt², Marjon H Cnossen¹

Affiliations

¹ Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands.
² Department of Clinical Pharmacology-Hospital Pharmacy, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
³ Department of Pediatric Hematology, Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Amsterdam, the Netherlands.
⁴ Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁵ Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, the Netherlands.
⁶ Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, the Netherlands.
⁸ Van Creveldkliniek, Center for Benign Haematology, Thrombosis and Haemostasis, University Medical Center Utrecht, Utrecht, the Netherlands.
⁹ Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
¹⁰ Department of Hematology, Maastricht University Medical Center+, Maastricht, the Netherlands.
¹¹ Department of Hematology, Haga Hospital, the Hague, the Netherlands.
¹² Department of Internal Medicine, Maxima Medical Center, Veldhoven, the Netherlands.
¹³ Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands.
¹⁴ Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Abstract

Background: Pharmacokinetic (PK)-guided dosing is used to individualize factor (F)VIII and FIX replacement therapy.

Objectives: This study investigates the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Methods: In this multicenter, prospective cohort study, people of all ages with hemophilia received prophylactic treatment with factor concentrates based on individual PK parameters. During follow-up, at least 4 measured FVIII/FIX levels per patient were compared with corresponding predicted levels obtained by Bayesian forecasting. Predictive performance was defined as adequate when ≥80% of measured FVIII/FIX levels were within ±25% of prediction (relative error). Additionally, mean absolute error and mean error were calculated. In post hoc analyses, predictive performance was assessed allowing maximum absolute errors of 1 (trough), 5 (mid), and 15 (peak) IU/dL. Five-point scale questionnaires addressed feasibility of PK guidance.

Results: We included 50 patients (median age, 19 years; range: 2-72 years). Median follow-up was 36 weeks. Seventy-one percent of levels (58% trough, 83% mid, and 80% peak) were within ±25% of prediction. Mean absolute errors were 0.8 (trough), 2.0 (mid), and 8.6 (peak) IU/dL. In post hoc analyses, 81% (trough), 96% (mid), and 82% (peak) of levels were within set limits. Patients reported low burden and high satisfaction.

Conclusion: PK-guided dosing was reliable according to post hoc analyses, based on low absolute errors that were regarded as clinically irrelevant in most cases. The predefined predictive performance was achieved in mid and peak factor levels but not in trough factor levels due to measurement inaccuracy. PK guidance also seemed feasible.

Keywords: factor IX; factor VIII; hemophilia A; hemophilia B; pharmacokinetics; preventive medicine.