A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A PatientsFunding This particular study was funded by the Dutch Innovation fund, which supplied funding to innovate current hemophilia treatment.
29 October 2019
20 February 2020
05 May 2020 (online)
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.
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.
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.
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