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

UK-EHL Outcomes Registry OPTI-CLOT; 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. Mathot; Marjon H. Cnossen

doi:10.1055/s-0040-1709522

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

UK-EHL Outcomes Registry OPTI-CLOT, 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. Mathot^*Marjon H. Cnossen

^*Corresponding author for this work

Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Research output: Contribution to journal › Article › Academic › peer-review

6 Citations (Scopus)

63 Downloads (Pure)

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

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.

Original language	English
Pages (from-to)	747-757
Number of pages	11
Journal	Thrombosis and Haemostasis
Volume	120
Issue number	5
DOIs	https://doi.org/10.1055/s-0040-1709522
Publication status	Published - 1-May-2020

Keywords

recombinant factor VIII-Fc
population
pharmacokinetics
child
validation
VON-WILLEBRAND-FACTOR
FACTOR-IX
AGE
SAMPLES
PLASMA
STAGE

Access to Document

10.1055/s-0040-1709522

A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A PatientsFinal publisher's version, 663 KBLicence: Taverne

Handle.net

Persistent link

Cite this

UK-EHL Outcomes Registry OPTI-CLOT, Bukkems, L. H., Heijdra, J. M., Mathias, M., Collins, P. W., Hay, C. R. M., Tait, R. C., Mangles, S., Myers, B., Evans, G., Bailiff, B., Curry, N., Payne, J., Austin, S., Goedhart, T. M. H. J., Leebeek, F. W. G., Meijer, K., Fijnvandraat, K., Chowdary, P., ... Cnossen, M. H. (2020). A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients. Thrombosis and Haemostasis, 120(5), 747-757. https://doi.org/10.1055/s-0040-1709522

@article{0ce2e98c45e54ad5b1c02d47190e8892,

title = "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 (FVIIIConclusion 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, VON-WILLEBRAND-FACTOR, FACTOR-IX, AGE, SAMPLES, PLASMA, STAGE",

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

year = "2020",

month = may,

day = "1",

doi = "10.1055/s-0040-1709522",

language = "English",

volume = "120",

pages = "747--757",

journal = "Thrombosis and Haemostasis",

issn = "0340-6245",

publisher = "GEORG THIEME VERLAG KG",

number = "5",

}

UK-EHL Outcomes Registry OPTI-CLOT, Bukkems, LH, Heijdra, JM, Mathias, M, Collins, PW, Hay, CRM, Tait, RC, Mangles, S, Myers, B, Evans, G, Bailiff, B, Curry, N, Payne, J, Austin, S, Goedhart, TMHJ, Leebeek, FWG, Meijer, K, Fijnvandraat, K, Chowdary, P, Mathot, RAA & Cnossen, MH 2020, 'A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients', Thrombosis and Haemostasis, vol. 120, no. 5, pp. 747-757. https://doi.org/10.1055/s-0040-1709522

A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients. / UK-EHL Outcomes Registry OPTI-CLOT; Bukkems, Laura H.; Heijdra, Jessica M. et al.
In: Thrombosis and Haemostasis, Vol. 120, No. 5, 01.05.2020, p. 747-757.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

AU - UK-EHL Outcomes Registry OPTI-CLOT

AU - Bukkems, Laura H.

AU - Heijdra, Jessica M.

AU - Mathias, Mary

AU - Collins, Peter W.

AU - Hay, Charles R. M.

AU - Tait, Robert C.

AU - Mangles, Sarah

AU - Myers, Bethan

AU - Evans, G.

AU - Bailiff, Benjamin

AU - Curry, Nicola

AU - Payne, Jeanette

AU - Austin, Steve

AU - Goedhart, Tine M. H. J.

AU - Leebeek, Frank W. G.

AU - Meijer, Karina

AU - Fijnvandraat, Karin

AU - Chowdary, Pratima

AU - Mathot, Ron A. A.

AU - Cnossen, Marjon H.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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 (FVIIIConclusion 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.

AB - 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 (FVIIIConclusion 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.

KW - recombinant factor VIII-Fc

KW - population

KW - pharmacokinetics

KW - child

KW - validation

KW - VON-WILLEBRAND-FACTOR

KW - FACTOR-IX

KW - AGE

KW - SAMPLES

KW - PLASMA

KW - STAGE

U2 - 10.1055/s-0040-1709522

DO - 10.1055/s-0040-1709522

M3 - Article

SN - 0340-6245

VL - 120

SP - 747

EP - 757

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

IS - 5

ER -