Comparison of FO – FOCE population parameter estimation methods in PhysPK 2.0 against NONMEM 7.3
Ignacio Gonzalez-Garcia (1), Manuel Prado-Velasco (2), Diego Garcia-Alvarez (2), Carlos Fernández-Teruel (1), Salvador Fudio (1)
(1) Pharma Mar S.A., Colmenar Viejo, Madrid, Spain, (2) PhysPK Unit, Empresarios Agrupados Internacional, Spain
Objectives: To develop a population pharmacokinetic model and compare the estimates using FO and FOCE in NONMEM 7.3 against PhysPK 2.0 by studying population parameters, interindividual and residual variability, weighted residuals and shrinkages, and sensitivity of solutions to perturbations and initial conditions, using real data obtained from different clinical trials.
Methods: The PK model was developed in NONMEM 7.3 [1] in order to speed up the development process and to focus the goal of this work. The final model was built and analysed also in PhysPK [2] and the results were compared with those of NONMEM using standard metrics. The sensitivity of NONMEM and PhysPK methods to changes in initial conditions or even in fixed population parameters used in covariates equations was quantified. PK data was taken from several clinical trials sponsored by Pharma Mar were the drug under development was given as single agent at different doses and different schemes.
Results: A three compartment model with linear disposition and elimination, with BSA effect on clearance and disposition, displayed the most accurate predictions. No major differences in parameters estimation were obtained by both software’s systems, but the sensitivity and robustness to initial conditions and parameter perturbations were different. A formal analysis of these ones and their implications in the development of PK models is presented.
Conclusions: PhysPK 2.0 is a new software for modelling and simulation of PK/PD/PBPK systems that can also be used for population parameter estimation. This work shows a preliminary study that compares FO and FOCE linear methods of PhysPK against the current gold standard FO and FOCE methods of NONMEM 7.3, with successful results. However, there are differences in the methods’ sensitivity to initial conditions and other parameter perturbations. A first analysis of them is presented for a better knowledge of their influence in FO and FOCE limitations.
References:
[1] Bauer RJ (Eds.) NONMEM Users Guides. 2015. ICON plc, Gaithersburg, Maryland, USA.
[2] M. Prado-Velasco, “PhysPK/EcosimPro: Sistema de modelado y simulación de sistemas fisiológicos. Metodología, arquitectura y aplicación a problemas PBPK/PK/PD,” in VI Jornadas de Modelización y Simulación en Biomedicina, 2015, p. 15.