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

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

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.

• 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