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

Laura H. Bukkems; Jessica M. Heijdra; Mary Mathias; Peter W. Collins; Charles R. M. Hay; Robert C. Tait; Sarah Mangles; Bethan Myers; G. Evans; Benjamin Bailiff; Nicola Curry; Jeanette Payne; Steve Austin; Tine M. H. J. Goedhart; Frank W. G. Leebeek; Karina Meijer; Karin Fijnvandraat; Pratima Chowdary; Ron A. A. Mathôt; Marjon H. Cnossen; for UK-EHL Outcomes Registry OPTI-CLOT Collaboration

doi:10.1055/s-0040-1709522

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

Laura H. Bukkems ^*

¹Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, The Netherlands

,

Jessica M. Heijdra^*

²Department of Pediatric Hematology, Erasmus University Medical Center – Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands

,

Mary Mathias

³Haemophilia Comprehensive Care Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom

,

Peter W. Collins

⁴Arthur Bloom Haemophilia Centre, School of Medicine, Cardiff University Hospital, Cardiff, United Kingdom

,

Charles R. M. Hay

⁵University Department of Haematology, Manchester University NHS Foundation Trust, Manchester, United Kingdom

,

Robert C. Tait

⁶Department of Haematology, Royal Infirmary, Glasgow, United Kingdom

,

Sarah Mangles

⁷Haemophilia, Haemostasis and Thrombosis Centre, Hampshire Hospitals NHS Foundation Trust, Basingstoke, United Kingdom

,

Bethan Myers

⁸Department of Haematology, United Lincolnshire Hospitals NHS Trust, Lincoln, United Kingdom

,

G. Evans

⁹Department of Haematology, East Kent Hospitals University NHS Foundation Trust, Kent, United Kingdom

,

Benjamin Bailiff

¹⁰Department Haematology and Blood Transfusion, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom

,

Nicola Curry

¹¹Oxford Haemophilia and Thrombosis Centre and Oxford NIHR BRC, Churchill Hospital, Oxford, United Kingdom

,

Jeanette Payne

¹²Department of PaediatricHaematology, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom

,

Steve Austin

¹³Centre for Haemostasis and Thrombosis, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

,

Tine M. H. J. Goedhart

²Department of Pediatric Hematology, Erasmus University Medical Center – Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands

,

Frank W. G. Leebeek

¹⁴Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

,

Karina Meijer

¹⁵Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

,

Karin Fijnvandraat

¹⁶Department of Pediatrics, Amsterdam University Medical Centers, The Netherlands

,

Pratima Chowdary ^*

¹⁷Katharine DormandyHaemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, United Kingdom

,

Ron A. A. Mathôt^*

¹Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, The Netherlands

,

Marjon H. Cnossen^*

²Department of Pediatric Hematology, Erasmus University Medical Center – Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands

,

for UK-EHL Outcomes Registry OPTI-CLOT Collaboration

› Institutsangaben

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.

Keywords

recombinant factor VIII-Fc - population - pharmacokinetics - child - validation

Volltext

Referenzen

References
1 Ahlberg A. Haemophilia in Sweden. VII. Incidence, treatment and prophylaxis of arthropathy and other musculo-skeletal manifestations of haemophilia A and B. Acta Orthop Scand Suppl 1965; 36 (Suppl. 77) 3-32
2 Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 2015; 125 (13) 2038-2044
3 Powell JS, Josephson NC, Quon D. , et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood 2012; 119 (13) 3031-3037
4 Mahlangu J, Powell JS, Ragni MV. , et al; A-LONG Investigators. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014; 123 (03) 317-325
5 Björkman S, Oh M, Spotts G. , et al. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood 2012; 119 (02) 612-618
6 Hazendonk HCAM, van Moort I, Mathôt RAA. , et al; OPTI-CLOT study group. Setting the stage for individualized therapy in hemophilia: What role can pharmacokinetics play?. Blood Rev 2018; 32 (04) 265-271
7 Nestorov I, Neelakantan S, Ludden TM, Li S, Jiang H, Rogge M. Population pharmacokinetics of recombinant factor VIII Fc fusion protein. ClinPharmacol Drug Dev 2015; 4 (03) 163-174
8 Björkman S, Blanchette VS, Fischer K. , et al; Advate Clinical Program Group. Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemost 2010; 8 (04) 730-736
9 Collins P, Chalmers E, Chowdary P. , et al. The use of enhanced half-life coagulation factor concentrates in routine clinical practice: guidance from UKHCDO. Haemophilia 2016; 22 (04) 487-498
10 Beal S, Sheiner L, Boeckmann A, Bauer R. NONMEM Users Guides; Available at: http://www.oalib.com/references/12847172 . Accessed March 23, 2020
11 Björkman S, Carlsson M, Berntorp E. Pharmacokinetics of factor IX in patients with haemophilia B. Methodological aspects and physiological interpretation. Eur J Clin Pharmacol 1994; 46 (04) 325-332
12 Diao L, Li S, Ludden T, Gobburu J, Nestorov I, Jiang H. Population pharmacokinetic modelling of recombinant factor IX Fc fusion protein (rFIXFc) in patients with haemophilia B. Clin Pharmacokinet 2014; 53 (05) 467-477
13 Carlsson M, Björkman S, Berntorp E. Multidose pharmacokinetics of factor IX: implications for dosing in prophylaxis. Haemophilia 1998; 4 (02) 83-88
14 Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive. Thromb Haemost 1999; 82 (05) 1456-1461
15 Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn 2008; 35 (04) 401-421
16 Byon W, Smith MK, Chan P. , et al. Establishing best practices and guidance in population modeling: an experience with an internal population pharmacokinetic analysis guidance. CPT Pharmacometrics Syst Pharmacol 2013; 2: e51
17 Nederlof A, Mathôt RAA, Leebeek FWG, Fijnvandraat K, Fischer K, Cnossen MH. ; “OPTI-CLOT” study group. Positioning extended half-life concentrates for future use: a practical proposal. Haemophilia 2018; 24 (05) e369-e372
18 Björkman S, Folkesson A, Jönsson S. Pharmacokinetics and dose requirements of factor VIII over the age range 3-74 years: a population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A. Eur J Clin Pharmacol 2009; 65 (10) 989-998
19 Garmann D, McLeay S, Shah A, Vis P, Maas Enriquez M, Ploeger BA. Population pharmacokinetic characterization of BAY 81-8973, a full-length recombinant factor VIII: lessons learned - importance of including samples with factor VIII levels below the quantitation limit. Haemophilia 2017; 23 (04) 528-537
20 Zhang Y, Roberts J, Tortorici M. , et al. Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A. J Thromb Haemost 2017; 15 (06) 1106-1114
21 Conlan MG, Folsom AR, Finch A. , et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70 (03) 380-385
22 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
23 Potgieter JJ, Damgaard M, Hillarp A. One-stage vs. chromogenic assays in haemophilia A. Eur J Haematol 2015; 94 (Suppl. 77) 38-44
24 Bowyer AE, Duncan EM, Antovic JP. Role of chromogenic assays in haemophilia A and B diagnosis. Haemophilia 2018; 24 (04) 578-583
25 Sommer JM, Moore N, McGuffie-Valentine B. , et al. Comparative field study evaluating the activity of recombinant factor VIII Fc fusion protein in plasma samples at clinical haemostasis laboratories. Haemophilia 2014; 20 (02) 294-300
26 Pruthi RK. Laboratory monitoring of new hemostatic agents for hemophilia. Semin Hematol 2016; 53 (01) 28-34
27 Dunn A. The long and short of it: using the new factor products. Hematology (Am Soc Hematol Educ Program) 2015; 2015: 26-32
28 Chelle P, Yeung CHT, Croteau SE. , et al. Development and Validation of a Population-Pharmacokinetic Model for Rurioctacog Alfa Pegol (Adynovate®): a Report on Behalf of the WAPPS-Hemo Investigators Ad Hoc Subgroup. Clin Pharmacokinet 2020; 59 (02) 245-256

Zusatzmaterial

Supplementary Material