Thromb Haemost 2020; 120(05): 747-757
DOI: 10.1055/s-0040-1709522
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

1  Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
,
Jessica M. Heijdra*
2  Department of Pediatric Hematology, Erasmus University Medical Center – Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands
,
Mary Mathias
3  Haemophilia Comprehensive Care Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
,
Peter W. Collins
4  Arthur Bloom Haemophilia Centre, School of Medicine, Cardiff University Hospital, Cardiff, United Kingdom
,
Charles R. M. Hay
5  University Department of Haematology, Manchester University NHS Foundation Trust, Manchester, United Kingdom
,
Robert C. Tait
6  Department of Haematology, Royal Infirmary, Glasgow, United Kingdom
,
Sarah Mangles
7  Haemophilia, Haemostasis and Thrombosis Centre, Hampshire Hospitals NHS Foundation Trust, Basingstoke, United Kingdom
,
Bethan Myers
8  Department of Haematology, United Lincolnshire Hospitals NHS Trust, Lincoln, United Kingdom
,
G. Evans
9  Department of Haematology, East Kent Hospitals University NHS Foundation Trust, Kent, United Kingdom
,
Benjamin Bailiff
10  Department Haematology and Blood Transfusion, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
,
Nicola Curry
11  Oxford Haemophilia and Thrombosis Centre and Oxford NIHR BRC, Churchill Hospital, Oxford, United Kingdom
,
Jeanette Payne
12  Department of PaediatricHaematology, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom
,
Steve Austin
13  Centre for Haemostasis and Thrombosis, St George's University Hospitals NHS Foundation Trust, London, United Kingdom
,
Tine M. H. J. Goedhart
2  Department of Pediatric Hematology, Erasmus University Medical Center – Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands
,
Frank W. G. Leebeek
14  Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
,
Karina Meijer
15  Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Karin Fijnvandraat
16  Department of Pediatrics, Amsterdam University Medical Centers, The Netherlands
,
17  Katharine DormandyHaemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, United Kingdom
,
Ron A. A. Mathôt*
1  Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
,
Marjon H. Cnossen*
2  Department of Pediatric Hematology, Erasmus University Medical Center – Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands
,
for UK-EHL Outcomes Registry OPTI-CLOT Collaboration› Author Affiliations
Funding This particular study was funded by the Dutch Innovation fund, which supplied funding to innovate current hemophilia treatment.
Further Information

Publication History

29 October 2019

20 February 2020

Publication Date:
05 May 2020 (online)

Abstract

Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required.

Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM).

Results A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (–1.0%, 95% CI: –9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients <12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children.

Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.

Authors' Contributions

L.H.B. and R.A.A.M. analyzed the data and developed the population pharmacokinetic model. J.M.H. collected and checked all clinical data from the EHL registry. R.A.A.M., M.H.C. and P.C. designed and supervised the study, while M.M., P.W.C., C.R.M.H., F.W.G.L., K.M., and K.F. gave critical guidance. Patient inclusion in the UK EHL registry was monitored by M.M., P.W.C., C.R.M.H., R.C.T., S.M., B.M., G.E., B.B., N.C., J.P., and S.A. The clinical case was treated by K.F. All authors contributed substantially to the writing and critical revision of the manuscript and approved the final draft.


Note

This study is a collaboration between the international multicenter OPTI-CLOT consortium (Patient tailOredPharmacokineTIc-guided dosing of CLOTting factor concentrate and desmopressin in bleeding disorders) and the United Kingdom – Extended Half-Life (UK-EHL) Outcome registry. OPTI-CLOT aims to implement PK-guided dosing of clotting factor concentrates by initiating studies that emphasize the impact of PK-guided dosing, by constructing prophylactic and on-demand population PK models, and by evaluating the cost-effectiveness of a PK-guided approach. The UK-EHL Outcome registry aims to evaluate the impact of EHLs on real world outcomes for patients with hemophilia and develop an evidence base for the introduction of new clinical strategies for improved patient outcomes. A list of the members of the “OPTI-CLOT” and UK-EHL outcome registry programs are available in [Supplementary Appendix A] (available in the online version).


* Shared first and last authorship.


Supplementary Material