Application of Physiologically-Based Pharmacokinetic/Pharmacodynamic Modelling in Oncology
Kristin Dickschen (1), Rolf Burghaus (2), Thomas Eissing (1), Thomas Gaub (1), Lars Küpfer (1), Jörg Lippert (2), Michael Block (1)
(1) Bayer Technology Services GmbH, Technology Development, Enabling Technologies, Computational Systems Biology, Leverkusen, Germany; (2) Bayer Pharma AG, Clinical Pharmacometrics, Wuppertal, Germany
Objectives: Physiologically-based (PB) modelling provides a useful tool to support research and development of oncological substances, comprising both small molecules and biologics.
Methods: We developed a PB model applicable to answer oncological questions. The model includes a detailed representation of the tumor pharmacokinetics (PK) and pharmacodynamics (PD), therefore enabling a sophisticated representation of all relevant processes at the physiological level for small molecules as well as for biologics. The presented PB model for oncology was developed by use of the systems biology software suite for PBPK and PD modeling, including PK-Sim® and MoBi®. It contains a structure which enables a detailed representation of the different required modeling levels including cellular to population level. It thus can address questions arising along the drug development process from early preclinical to clinical development and species extrapolation [1-4]. Specific processes included in the model for antibody drug conjugates are on-target and off-target binding, FcRn binding as well as processes regarding target receptor availability and receptor internalization [5]. In addition, a PD model was integrated in order to be able to represent tumor growth [6]. The model was designed in a manner ready to address both; the full PK for biologics as well as for small molecules within one structure.
Results: By means of different examples it could be demonstrated that the presented PB model for oncology is well able to represent the PK and related tumor growth dynamics of small molecules as well as antibodies and antibody drug conjugates in important preclinical species.
Conclusions: The presented PB model provides useful insight into scenarios relevant for the clinical situation.
References:
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