Saez-Rodriguez Group

Systems biomedicine

Integrative physiological-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling of drug, efficiency and toxicity

Systems Pharmacology is an emerging field which combines the principle of Pharmacology and Systems Biology. The field of Pharmacology aims to understand how therapeutic agents are absorbed, distributed, metabolized, and excreted (ADME) once administered into the organism and how such therapeutic agents exert the pharmacological effects at their target sites. With the combination to the principles of Systems Biology, Systems Pharmacology provides a deeper understanding of the pharmacological effects ranged from the molecular levels up to the whole organism and allows to perform the scaling of drug concentrations from one organism to the others. The field of Systems Pharmacology offers a broad range of applications including quantitative and time-course predictions of drug-to-drug interactions (DDI’s), drug combination therapies, as well as drug toxicities in different types of organs.

In Systems Pharmacology, mathematical models are commonly used to describe the processes of pharmacokinetics (PK) i.e what the body does to the drug and pharmacodynamics (PD) i.e what the drug does to the body. When the classical PK/PD approach takes into account the prior information regarding the anatomy and the physiology of the whole organism the resulting model is called physiological-based pharmacokinetic/pharmacodynamic model (PBPK/PD). Such a model aims for a mechanistic understanding of the physiological processes that describe the drug’s ADME properties as well as the dose-response relationship within an organism in a quantitative and time-dependent manner.
Nowadays, PBPK models are viewed as a useful tool by the regulatory agencies at the lead optimization stage of drug discovery, at the selection stage of drug development (Zhuang and Lu Acta Pharm Sin b, 2016),(Shepard et al CPT Pharmacometrics Syst Pharmacol, 2015).

We work in collaboration with Dr. Lars Kuepfer at Bayer GmbH for the development of PBPK/PD models (Kuepfer et al CPT Pharmacometrics Syst Pharmacol, 2016) in the context of cancer. Since PBPK models describe the physiology of an organism at high level of detail they can, therefore, be used to simulate the PK profiles of specific cancer patient subgroups with individualized physiology. Furthermore, PD models describe the dose-response relationship; the change in effect on an organism caused by different levels of drug exposure at the site of action. We are working to include patient specific characteristics (e.g genomic, epigenomic, proteomic) to understand inter-subject variability in drug-response.

In addition, within the framework of the IMI-2 TransQST project, we work with academic and industrial partners to integrate logical models of cellular regulatory networks onto the PBPK/PD model. The integrative PBPK/PD model is expected to provide new insights on the mechanisms of regulation of the PK/PD process from the molecular level towards the phenotypic outcomes in terms of drug toxicity. Our current interest is focused on depicting the pathophysiological mechanisms of drug-induced liver injury (DILI) and drug-induced kidney injury (DIKI) while the developed computational tools and analytical pipelines will also be applicable to the study of drug’s toxicological effects in other organs.

A physiological-based pharmacokinetic/pharmacodynamic (PBPK) model comprises multiple organ compartments that represent the physiology of the whole organism. Such a model can be used to study the absorption, distribution, metabolism, and elimination (ADME) processes of administrative compounds (e.g. drugs) which link to molecular and phenotypic outcomes, and it can also be extrapolated between different organisms (e.g. between rodent species and human).