OC 27.5 - Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B (OPTI-CLOT TARGET study) – Preliminary results

Sunday, July 10, 2022

3:45 PM – 4:00 PM

Location: ExCel Center, ICC Capital Suite Room 2-4

Presentation Format: In-Person

Presenting Author(s)

Tine Goedhart, MD

PhD student
Erasmus MC Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
Rotterdam, Zuid-Holland, Netherlands

Co-Author(s)

LB

Laura Bukkems

PhD student
Department of Clinical Pharmacology - Hospital Pharmacy, Amsterdam UMC, University of Amsterdam, Amsterdam
Amsterdam, Noord-Holland, Netherlands
Michiel Coppens, MD, PhD

Medical Specialist
Department of Vascular Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
KF

Karin Fijnvandraat

Professor of Pediatric Hematology
Department of Pediatric Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam, Noord-Holland, Netherlands
SS

Saskia E.M. Schols

Internist-hematologist
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands. Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands
Nijmegen, Gelderland, Netherlands
Roger E.G. Schutgens, MD, PhD, MSc

Internist-hematologist, Professor
Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht and University Utrecht, Utrecht, The Netherlands
Utrecht, Utrecht, Netherlands
JE

Jeroen C.J. Eikenboom

Professor, Internist, Head of Div. T&H
Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
FH

Floor Heubel-Moenen

Internist hematologist
Department of Hematology, Maastricht University Medical Center, Maastricht, the Netherlands
Maastricht, Limburg, Netherlands
PY

Paula Ypma

Internist hematologist
Department of Hematology, Haga Hospital, The Hague, Netherlands
The Hague, Zuid-Holland, Netherlands
LN

Laurens Nieuwenhuizen

Internist-hematologist
Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands. Department of Hematology, Maxima Medical Center, Eindhoven, The Netherlands.
Eindhoven, Noord-Brabant, Netherlands
Karina Meijer, MD, PhD

MD, PhD, Internist-haematologist, Professor
Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Groningen, Groningen, Netherlands
Frank W.G. Leebeek, MD, PhD

Professor and Head of Department of Hematology
Erasmus MC, University Medical Center Rotterdam, The Netherlands
Rotterdam, Zuid-Holland, Netherlands
RM

Ron A.A. Mathôt

Professor, Clinical pharmacologist, PharmD, PhD
Department of Hospital Pharmacy & Clinical Pharmacology, Amsterdam UMC – location AMC, The Netherlands.
Amsterdam, Noord-Holland, Netherlands
MC

Marjon H. Cnossen

Associate professor, pediatric hematologist, MD, PhD
Department of Pediatric Hematology, Erasmus MC – Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
Rotterdam, Zuid-Holland, Netherlands

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

Aims: Investigate the predictive performance of PK-guided prophylactic dosing of factor concentrates in hemophilia patients.

Methods: In this multicenter, prospective cohort study, hemophilia patients of all ages on prophylaxis with standard half-life (SHL) and extended half-life (EHL) factor concentrates received PK-guided dosing. Treating physicians set individual target levels based on previous FVIII/FIX levels, physical activities and bleeding phenotype. During 9 months follow-up, at least four measured FVIII/FIX levels per patient were compared to corresponding predictions obtained by Bayesian forecasting. Predictive performance was adequate when ≥80% of the measured FVIII/FIX levels were within ±25% of the prediction. Bias and accuracy were calculated using mean error (ME) and mean absolute error (MAE), respectively. During post-hoc analysis, predictive performance was assessed allowing maximal difference of 1 (trough), 5 (mid) and 15 (peak) IU/dL. Ethical approval and informed consent was obtained.

Results: Fifty patients were included (Table 1). Twenty-seven patients completed the study (January, 2022). Median targeted FVIII/FIX trough level under PK-guidance was 2 IU/dL [IQR 1-4]. Predictive performance of 189 levels is shown in Figure 1. Sixty-six percent of levels (54% trough, 77% mid, 72% peak) were within ±25% of prediction. MAE was 0.7 (trough), 2.6 (mid) and 10.5 (peak) IU/dL. According to post-hoc analysis, 77% (trough), 92% (mid) and 78% (peak) of levels were within set limits. Patients who completed the study had a median number of total and spontaneous bleeds of one (IQR 0-3) and zero (IQR 0-1), respectively.

Conclusion(s): The prespecified predictive performance target was not achieved, partly due to high measurement error especially in trough levels. In our opinion, the predictive performance of PK-guidance in clinical practice is better represented by post-hoc analysis, the ME and MAE. These low errors were regarded as clinically irrelevant in most cases.