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Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)

BACKGROUND: Hemophilia is an inherited bleeding disorder caused by a deficiency in a specific clotting factor. This results in spontaneous bleeding episodes and eventual arthropathy. The mainstay of hemophilia treatment is prophylactic replacement of the missing factor, but an optimal regimen remain...

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Autores principales: McEneny-King, Alanna, Foster, Gary, Iorio, Alfonso, Edginton, Andrea N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: JMIR Publications 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177737/
https://www.ncbi.nlm.nih.gov/pubmed/27927609
http://dx.doi.org/10.2196/resprot.6559
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author McEneny-King, Alanna
Foster, Gary
Iorio, Alfonso
Edginton, Andrea N
author_facet McEneny-King, Alanna
Foster, Gary
Iorio, Alfonso
Edginton, Andrea N
author_sort McEneny-King, Alanna
collection PubMed
description BACKGROUND: Hemophilia is an inherited bleeding disorder caused by a deficiency in a specific clotting factor. This results in spontaneous bleeding episodes and eventual arthropathy. The mainstay of hemophilia treatment is prophylactic replacement of the missing factor, but an optimal regimen remains to be determined. Rather, individualized prophylaxis has been suggested to improve both patient safety and resource utilization. However, uptake of this approach has been hampered by the demanding sampling schedules and complex calculations required to obtain individual estimates of pharmacokinetic (PK) parameters. The use of population pharmacokinetics (PopPK) can alleviate this burden by reducing the number of plasma samples required for accurate estimation, but few tools incorporating this approach are readily available to clinicians. OBJECTIVE: The Web-accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) project aims to bridge this gap by providing a Web-accessible service for the reliable estimation of individual PK parameters from only a few patient samples. This service is predicated on the development of validated brand-specific PopPK models. METHODS: We describe the data analysis plan for the development and evaluation of each PopPK model to be incorporated into the WAPPS-Hemo platform. The data sources and structure of the dataset are discussed first, followed by the procedures for handling both data below limit of quantification (BLQ) and absence of such BLQ data. Next, we outline the strategies for building the appropriate structural and covariate models, including the possible need for a process algorithm when PK behavior varies between subjects or significant covariates are not provided. Prior to use in a prospective manner, the models will undergo extensive evaluation using a variety of techniques such as diagnostic plots, bootstrap analysis and cross-validation. Finally, we describe the incorporation of a validated PopPK model into the Bayesian post hoc model to produce individualized estimates of PK parameters. RESULTS: Dense PK data has been collected for more than 20 brands of factor concentrate from both industry-sponsored and investigator-driven studies. The model development process is underway for the majority of molecules, with refinement and validation to be completed in 2017. Further, the WAPPS-Hemo co-investigator network has contributed more than 300 PK assessments for use in model development and evaluation. This constitutes the largest repository of this type of PK data globally. CONCLUSIONS: The WAPPS-Hemo service aims to eliminate barriers to the uptake of individualized PK-tailored hemophilia treatment. By incorporating this tool into routine practice, clinicians can implement a personalized dosing strategy without performing rigorous sampling or complex calculations. This service is centred on validated models developed according to the robust approach to PopPK modeling described herein. CLINICALTRIAL: ClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 (Archived by WebCite at http://www.webcitation.org/6mRIXJh55)
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spelling pubmed-51777372017-01-03 Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) McEneny-King, Alanna Foster, Gary Iorio, Alfonso Edginton, Andrea N JMIR Res Protoc Protocol BACKGROUND: Hemophilia is an inherited bleeding disorder caused by a deficiency in a specific clotting factor. This results in spontaneous bleeding episodes and eventual arthropathy. The mainstay of hemophilia treatment is prophylactic replacement of the missing factor, but an optimal regimen remains to be determined. Rather, individualized prophylaxis has been suggested to improve both patient safety and resource utilization. However, uptake of this approach has been hampered by the demanding sampling schedules and complex calculations required to obtain individual estimates of pharmacokinetic (PK) parameters. The use of population pharmacokinetics (PopPK) can alleviate this burden by reducing the number of plasma samples required for accurate estimation, but few tools incorporating this approach are readily available to clinicians. OBJECTIVE: The Web-accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) project aims to bridge this gap by providing a Web-accessible service for the reliable estimation of individual PK parameters from only a few patient samples. This service is predicated on the development of validated brand-specific PopPK models. METHODS: We describe the data analysis plan for the development and evaluation of each PopPK model to be incorporated into the WAPPS-Hemo platform. The data sources and structure of the dataset are discussed first, followed by the procedures for handling both data below limit of quantification (BLQ) and absence of such BLQ data. Next, we outline the strategies for building the appropriate structural and covariate models, including the possible need for a process algorithm when PK behavior varies between subjects or significant covariates are not provided. Prior to use in a prospective manner, the models will undergo extensive evaluation using a variety of techniques such as diagnostic plots, bootstrap analysis and cross-validation. Finally, we describe the incorporation of a validated PopPK model into the Bayesian post hoc model to produce individualized estimates of PK parameters. RESULTS: Dense PK data has been collected for more than 20 brands of factor concentrate from both industry-sponsored and investigator-driven studies. The model development process is underway for the majority of molecules, with refinement and validation to be completed in 2017. Further, the WAPPS-Hemo co-investigator network has contributed more than 300 PK assessments for use in model development and evaluation. This constitutes the largest repository of this type of PK data globally. CONCLUSIONS: The WAPPS-Hemo service aims to eliminate barriers to the uptake of individualized PK-tailored hemophilia treatment. By incorporating this tool into routine practice, clinicians can implement a personalized dosing strategy without performing rigorous sampling or complex calculations. This service is centred on validated models developed according to the robust approach to PopPK modeling described herein. CLINICALTRIAL: ClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 (Archived by WebCite at http://www.webcitation.org/6mRIXJh55) JMIR Publications 2016-12-07 /pmc/articles/PMC5177737/ /pubmed/27927609 http://dx.doi.org/10.2196/resprot.6559 Text en ©Alanna McEneny-King, Gary Foster, Alfonso Iorio, Andrea N Edginton. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 07.12.2016. https://creativecommons.org/licenses/by/2.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0/ (https://creativecommons.org/licenses/by/2.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on http://www.researchprotocols.org, as well as this copyright and license information must be included.
spellingShingle Protocol
McEneny-King, Alanna
Foster, Gary
Iorio, Alfonso
Edginton, Andrea N
Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)
title Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)
title_full Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)
title_fullStr Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)
title_full_unstemmed Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)
title_short Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)
title_sort data analysis protocol for the development and evaluation of population pharmacokinetic models for incorporation into the web-accessible population pharmacokinetic service - hemophilia (wapps-hemo)
topic Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177737/
https://www.ncbi.nlm.nih.gov/pubmed/27927609
http://dx.doi.org/10.2196/resprot.6559
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