Abstract
Fanhdi/Alphanate is a plasma derived factor VIII concentrate used for treating hemophilia A, for which there has not been any dedicated model describing its pharmacokinetics (PK). A population PK model was developed using data extracted from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project. WAPPS-Hemo provided individual PK profiles for hemophilia patients using sparse observations as provided in routine clinical care by hemophilia centers. Plasma factor activity measurements and covariate data from hemophilia A patients on Fanhdi/Alphanate were extracted from the WAPPS-Hemo database. A population PK model was developed using NONMEM and evaluated for suitability for Bayesian forecasting using prediction-corrected visual predictive check (pcVPC), cross validation, limited sampling analysis and external evaluation against a population PK model developed on rich sampling data. Plasma factor activity measurements from 92 patients from 12 centers were used to derive the model. The PK was best described by a 2-compartment model including between subject variability on clearance and central volume, fat free mass as a covariate on clearance, central and peripheral volumes, and age as covariate on clearance. Evaluations showed that the developed population PK model could predict the PK parameters of new individuals based on limited sampling analysis and cross and external evaluations with acceptable precision and bias. This study shows the feasibility of using real-world data for the development of a population PK model. Evaluation and comparison of the model for Bayesian forecasting resulted in similar results as a model developed using rich sampling data.
Highlights
Fanhdi (Grifols, Barcelona, Spain) and Alphanate (Grifols, Los Angeles, CA, USA) are plasma derived factor VIII (FVIII) concentrates containing von Willebrand factorJournal of Pharmacokinetics and Pharmacodynamics (2019) 46:427–438(VWF) that are used for treating hemophilia A and for which no specific model describing their pharmacokinetics (PK) has been developed
A population PK model was developed using data extracted from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project
A population PK model was developed using NONMEM and evaluated for suitability for Bayesian forecasting using prediction-corrected visual predictive check, cross validation, limited sampling analysis and external evaluation against a population PK model developed on rich sampling data
Summary
(VWF) that are used for treating hemophilia A and for which no specific model describing their pharmacokinetics (PK) has been developed. These two concentrates are assumed the same product since they use same manufacturing process [1]. Patients with severe hemophilia A, defined as an endogenous FVIII activity lower than 0.01 IU/mL, often suffer spontaneous, and recurring joint bleeds, eventually leading to arthropathy. Prophylactic replacement therapy has become the standard treatment for severe hemophilia A. It consists of regular injections of FVIII concentrate and aims at preventing spontaneous joint bleeds by achieving a trough FVIII activity greater than 0.01 IU/mL [4, 5]. As a trough level of 0.01 IU/mL does not prevent all patients from bleeding, higher targets are considered when individualizing treatment [6]
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