Bridging the gap between open and specialized modelling tools in PBPK/PK/PD with PhysPK/EcosimPro modelling system: PBPK model of methotrexate and 6-mercaptopurine in humans with focus in reusability and multilevel modelling features
Manuel Prado-Velasco
EcosimPro/PhysPK Unit, Empresarios Agrupados Internacional, Spain
Objectives: To validate a novel modelling and simulation biomedical tool, PhysPK/EcosimPro, through the building of a MTX and 6-MP PBPK model using a technique that promotes the reuse of models with different description scales (from group of cells to group of tissues).
Methods: A PBPK model for MTX and 6-MP, including stomach, gut lumen, liver, and kidney tissues with different modelling approaches (perfused limited and membrane limited), and description scales (kidney described through glomerulus’ dynamics), has been built using the novel PhysPK/EcosimPro M&S tool [1]. The model was previously developed and validated in adults and children by Ogungbenro et al. [2-3], and considers enterohepatic flow, non-linear binding, and inhibition of 6-MP first-pass effect by MTX.
PhysPK/EcosimPro is a new M&S software for physiological and therapeutic systems that combines cutting-edge methodologies and technologies to provide:
• Specialized pre-built and protected extended PBPK/PK/PD human and animal models and devices models
• Independence of physiological model formulation from algorithmic issues
• Open GUI environment to build multi-level models according to a three-layer architecture for mechanisms, physiological / machine elements, and signal processing elements
These features are the basis for reusing models by adding or substituting mechanisms and subsystems at different levels.
The cited model has been built with PhysPK from scratch, and from Bischof et al. model [4], modifying several mechanisms, and tissues.
The model is finally extended to include a high-flux dialysis membrane connected to a patient. High MTX infusion doses followed by high-flux dialysis is performed in the model and compared with published results [5].
Results: Concentration-time profiles agree with those published in [2-3]. The extended model reproduced the behavior of MTX concentration for pediatric patients submitted to dialysis (F-40 and F-80 Fresenius membranes) [5]. The model building methodology and technology based on PhysPK/EcosimPro has been successfully validated.
Conclusion: Reusability and multilevel modelling have been successfully tested in PhysPK/EcosimPro through the development of a PBPK model for MTX and 6-MP. This software tool combines a non-algorithmic and object-oriented modelling methodology with a three-layer specialized biomedical modelling architecture to fill the gap between current open and specialized commercial modelling tools in this arena.
References:
[1] 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.
[2] K. Ogungbenro and L. Aarons, “Physiologically based pharmacokinetic modelling of methotrexate and 6-mercaptopurine in adults and children. Part 2: 6-mercaptopurine and its interaction with methotrexate,” J. Pharmacokinet. Pharmacodyn., vol. 41, no. 2, pp. 173–185, 2014.
[3] K. Ogungbenro and L. Aarons, “Physiologically based pharmacokinetic modelling of methotrexate and 6-mercaptopurine in adults and children. Part 1: Methotrexate,” J. Pharmacokinet. Pharmacodyn., vol. 41, no. 2, pp. 159–171, 2014.
[4] K. B. Bischoff, R. L. Dedrick, D. S. Zaharko, and J. a Longstreth, “Methotrexate pharmacokinetics.,” J. Pharm. Sci., vol. 60, no. 8, pp. 1128–1133, 1971.
[5] J. M. Saland, P. J. Leavey, R. O. Bash, E. Hansch, G. S. Arbus, and R. Quigley, “Effective removal of methotrexate by high-flux hemodialysis,” Pediatr. Nephrol., vol. 17, no. 10, pp. 825–829, 2002.
