Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients

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.Electronic supplementary materialThe online version of this article (10.1007/s10928-019-09637-4) contains supplementary material, which is available to authorized users.

Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS‐Hemo project

“…Robust validation of the predictive characteristics of WAPPS‐Hemo has been published, 4 confirming the general assessment of Bayesian forecasting applied to haemophilia, 5 as well as the general approach to modelling 6 and full details of models of specific interest 7,8 . However, a formal assessment of the performance for the entire set of WAPPS‐Hemo models has yet to be published.…”

“…Moreover, in the event that no clinical trial data were available, we have been able to create PopPK models from WAPPS‐Hemo data alone. Examples include Adynovate 7 and Alphanate/Fanhdi 8 . In practice, PK requests for Alphanate/Fanhdi and Adynovate were initially modelled using a generic factor VIII model.…”

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

“…Bootstrap CIs for Fanhdi/Alphanate 8 and Fanhdi/Alphanate/Koate models with and without brand covariate on V1 (centered at median fat free mass 50.5 kg and age 25 years; Central and inter-compartmental clearance CL pop , Q pop : L/h; Central and peripheral volume of distribution V1 pop , V2 pop : L).…”

Orphan drugs pharmacotherapeutic management in Hospital Pharmacy

“…WAPPS Hemo® ha sido desarrollada independiente de la industria farmacéutica y permite la estimación en 24h de todos los factores aplicando covariables como la edad, el peso, le altura, grupo sanguíneo o el factor de Von Willebrand. Además esta herramienta se puede ligar a diferentes apps (myWAPPS, florio, Haemoassist) (46,47).…”