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

Abstract

BackgroundHemophilia 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.ObjectiveThe 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.MethodsWe 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.ResultsDense 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.ConclusionsThe 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.ClinicalTrialClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 ...

Development of a Web-Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS-Hemo): Study Protocol

“…All developed models and methodological issues involved in the development and validation of models are reported in separate scientific reports [14,19]. In brief, assessment of validity of a system like WAPPS-Hemo is a complex process which will be covered in a stepwise fashion.…”

“…Further, population pharmacokinetics models for the factor concentrates for which concentration-time data are available will be established. The model development process is described in a separate scientific report [14]. The extended version of this report will be available as part of the study documentation, while a synthetic version will be submitted for publication.…”

“…A congruency check will be performed on the submitted input data. Details about the development and evaluation of the underlying population pharmacokinetics models as well as details of the postmodelling Bayesian estimation are provided in a separate paper [14]. …”

Clinical application of Web Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS‐Hemo): Patterns of blood sampling and patient characteristics among clinician users

“…18 Implementation of population pharmacokinetics (PopPK) for haemophilia A and haemophilia B has facilitated a practical approach to individualizing prophylactic factor replacement regimens informed by a patient's PK profile. 6,23 The Web Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) is a globally available service with specific models for most commercially available FVIII and FIX CFCs. 15,19,20 Historically, incorporation of PK into routine clinical practice has been impeded by the rigorous sampling required for classical PK methodology, 21,22 limited access to provider-friendly tools for PK analysis, and provider and patient uncertainty about the magnitude of improvement to be gained by adding PK information to decision-making.…”

Replacement therapy during surgery in von Willebrand disease needs personalization

“…In view of the issues discussed above, it seems, indeed, very important for a better personalization of replacement in VWD. This is not as “easy” as it is in haemophilia, where population PK models have been published and are implemented in clinical practice . The complex variation between VWD concentrate brands and VWD types makes population PK and personalized care more difficult to develop in VWD and, so far, prediction of levels during surgery using parameters such as blood group or pharmacokinetics does not seem reliable .…”