Clinical Pharmacology – Biomolecular
Translational PK/PD modeling is the integration of in silico, in vitro and in vivo preclinical data with mechanism based models to predict the effects of drugs in humans or across different biological systems.
Successful implementation of translational PK/PD modeling and simulation early in the drug discovery process can have substantial impact on overall efficiency and quality of decision making in pharmaceutical research.
In this presentation 3 case studies are presented, outlining successful implementation of translational PK/PD modeling in the development of different biotherapeutic modalities, impacting design/ selection of lead compounds and prediction of clinical efficacious doses and regimens.
In the first case study a site of action binding model for mAbs and Fc-fusions is described, based upon a target mediated drug disposition model. Application of the model for Kd optimization, human efficacious dose prediction and uncertainty analysis in clinical studies is shown. The importance of determining ‘system specific’ parameters, or biomeasures, is highlighted.
In the second case study a translational frame work for antibody drug conjugates (ADCs) is show-cased. A simple modeling approach is demonstrated first- capable of determining efficacious concentration using only mouse PK and tumor growth inhibition data. Toxicity data can also be included to estimate therapeutic index. Next, a multiscale mechanistic model is presented which can integrate cellular measures, PK and PD to answer feasibility questions and predict clinical efficacious response. Use of this model to select clinical dosing regimen and clinical diagnostics for an anti-CD22 ADC Inotuzumab is shown.
Finally, a multi-scale mechanistic model to guide target evaluation, drug design and clinical translation of CD3 bispecific T-celling retargeting compounds is presented. These molecules can tether resting T-cells to tumor cells, leading to T-cell activation and serial lysis of tumor cells. The model is based on the premise that T-cell activation is driven by the formation of a trimolecular complex (hereafter trimer) between the bispecific construct, the T-cell and the tumor cell, mimicking the immune synapse. The trimer concentration is calculated from CD3 and tumor target expression, cell numbers and Kd values. The trimer formation model can be coupled to PK, T-cell kinetic and tumor cell killing models. A case study describing use of the model to profile a P-cadherin/CD3 bispecific molecule is presented.