Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use

Background Population pharmacokinetics (popPK) has been reliably leveraged to generate individual PK in hemophilia patients. Specific popPK models are suited to predict individual PK under a variety of scenarios that may not be captured by clinical trials, allowing for individualized prophylactic tr...

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Autores principales:	Dagmar M. Hajducek, Fitri Primacakti, Novie Chozie, Roser Mir, Alanna McEneny-King, Alfonso Iorio, Andrea Edginton
Formato:	article
Lenguaje:	EN
Publicado:	SAGE Publishing 2021
Materias:	Diseases of the blood and blood-forming organs RC633-647.5
Acceso en línea:	https://doaj.org/article/def7f90629ae409f9a18f4b66c5c71e4
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spelling	oai:doaj.org-article:def7f90629ae409f9a18f4b66c5c71e42021-11-30T23:33:27ZDerivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use2634-853510.1177/26348535211062229https://doaj.org/article/def7f90629ae409f9a18f4b66c5c71e42021-11-01T00:00:00Zhttps://doi.org/10.1177/26348535211062229https://doaj.org/toc/2634-8535Background Population pharmacokinetics (popPK) has been reliably leveraged to generate individual PK in hemophilia patients. Specific popPK models are suited to predict individual PK under a variety of scenarios that may not be captured by clinical trials, allowing for individualized prophylactic treatment. The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project generates individually predicted pharmacokinetic profiles relying on concentrate-specific popPK models used for Bayesian forecasting. Objective Specification of a popPK model for the plasma-derived factor VIII (FVIII) concentrate Koate-DVI and its suitability for pharmacokinetic estimation in low-dose scenarios. Methods A popPK model was developed for Koate-DVI WAPPS-Hemo PK data in combination with the existing WAPPS-Hemo Fanhdi/Alphanate model derivation dataset using nonlinear mixed effects modelling, and was validated via cross-validation and prediction-corrected Visual Predictive Checks (pcVPC). Bootstrap and PK outcomes between the Fanhdi/Alphanate and the Fanhdi/Alphanate/Koate models were compared, and the relative error distributions from a limited sampling analysis (LSA) under the latter model for low and normal doses (10 vs 50 IU/kg) and inclusion/exclusion of pre-dose measurements. Results A Fanhdi/Alphanate/Koate model was derived (126 patients, ages 1–71 years) after deeming a Koate-brand covariate not clinically significant, resulting in similar parameter estimates than the Fanhdi/Alphanate model with satisfactory goodness of fit, cross-validation and pcVPC results. Low-dose predictions resulted in a higher accuracy and slightly lower precision of half-life ( β -phase) and time to 2% trough (TAT2%) estimates than normal dose (median absolute bias for half-life: 0.12 vs 0.5%; median interquartile range, IQR: 11.79% vs 9.95%). Precision improved under pre-dose designs by 2 to 3% and remained similar between 5- and 2-sample designs (IQR reduction<1.8%). Conclusions The Fanhdi/Alphanate/Koate model is appropriate for Bayesian forecasting in the WAPPS-Hemo platform, providing a comparable prediction capability for low and normal dosing regimens (10 vs 50 IU/Kg).Dagmar M. HajducekFitri PrimacaktiNovie ChozieRoser MirAlanna McEneny-KingAlfonso IorioAndrea EdgintonSAGE PublishingarticleDiseases of the blood and blood-forming organsRC633-647.5ENPlasmatology, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diseases of the blood and blood-forming organs RC633-647.5
spellingShingle	Diseases of the blood and blood-forming organs RC633-647.5 Dagmar M. Hajducek Fitri Primacakti Novie Chozie Roser Mir Alanna McEneny-King Alfonso Iorio Andrea Edginton Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use
description	Background Population pharmacokinetics (popPK) has been reliably leveraged to generate individual PK in hemophilia patients. Specific popPK models are suited to predict individual PK under a variety of scenarios that may not be captured by clinical trials, allowing for individualized prophylactic treatment. The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project generates individually predicted pharmacokinetic profiles relying on concentrate-specific popPK models used for Bayesian forecasting. Objective Specification of a popPK model for the plasma-derived factor VIII (FVIII) concentrate Koate-DVI and its suitability for pharmacokinetic estimation in low-dose scenarios. Methods A popPK model was developed for Koate-DVI WAPPS-Hemo PK data in combination with the existing WAPPS-Hemo Fanhdi/Alphanate model derivation dataset using nonlinear mixed effects modelling, and was validated via cross-validation and prediction-corrected Visual Predictive Checks (pcVPC). Bootstrap and PK outcomes between the Fanhdi/Alphanate and the Fanhdi/Alphanate/Koate models were compared, and the relative error distributions from a limited sampling analysis (LSA) under the latter model for low and normal doses (10 vs 50 IU/kg) and inclusion/exclusion of pre-dose measurements. Results A Fanhdi/Alphanate/Koate model was derived (126 patients, ages 1–71 years) after deeming a Koate-brand covariate not clinically significant, resulting in similar parameter estimates than the Fanhdi/Alphanate model with satisfactory goodness of fit, cross-validation and pcVPC results. Low-dose predictions resulted in a higher accuracy and slightly lower precision of half-life ( β -phase) and time to 2% trough (TAT2%) estimates than normal dose (median absolute bias for half-life: 0.12 vs 0.5%; median interquartile range, IQR: 11.79% vs 9.95%). Precision improved under pre-dose designs by 2 to 3% and remained similar between 5- and 2-sample designs (IQR reduction<1.8%). Conclusions The Fanhdi/Alphanate/Koate model is appropriate for Bayesian forecasting in the WAPPS-Hemo platform, providing a comparable prediction capability for low and normal dosing regimens (10 vs 50 IU/Kg).
format	article
author	Dagmar M. Hajducek Fitri Primacakti Novie Chozie Roser Mir Alanna McEneny-King Alfonso Iorio Andrea Edginton
author_facet	Dagmar M. Hajducek Fitri Primacakti Novie Chozie Roser Mir Alanna McEneny-King Alfonso Iorio Andrea Edginton
author_sort	Dagmar M. Hajducek
title	Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use
title_short	Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use
title_full	Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use
title_fullStr	Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use
title_full_unstemmed	Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use
title_sort	derivation of a pharmacokinetic model to include a plasma-derived, von willebrand factor-containing factor viii (koate-dvi) concentrate and its low-dose use
publisher	SAGE Publishing
publishDate	2021
url	https://doaj.org/article/def7f90629ae409f9a18f4b66c5c71e4
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Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use

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