Modeling, simulation, and translation framework for the preclinical development of monoclonal antibodies

Abstract

The industry-wide biopharmaceutical (i.e., biologic, biotherapeutic) pipeline has been growing at an astonishing rate over the last decade with the proportion of approved new biological entities to new chemical entities on the rise. As biopharmaceuticals appear to be growing in complexity in terms of their structure and mechanism of action, so are interpretation, analysis, and prediction of their quantitative pharmacology. We present here a modeling and simulation (M&S) framework for the successful preclinical development of monoclonal antibodies (as an illustrative example of biopharmaceuticals) and discuss M&S strategies for its implementation. Critical activities during early discovery, lead optimization, and the selection of starting doses for the first-in-human study are discussed in the context of pharmacokinetic-pharmacodynamic (PKPD) and M&S. It was shown that these stages of preclinical development are and should be reliant on M&S activities including systems biology (SB), systems pharmacology (SP), and translational pharmacology (TP). SB, SP, and TP provide an integrated and rationalized framework for decision making during the preclinical development phase. In addition, they provide increased target and systems understanding, describe and interpret data generated in vitro and in vivo, predict human PKPD, and provide a rationalized approach to designing the first-in-human study.

Fig. 1

Summary of the model-based preclinical development framework for biopharmaceuticals. Boxes with dotted lines represent modeling and simulation specific activities ideally implemented during preclinical development

Fig. 2

General scheme of target-mediated drug disposition (TMDD) assuming the target is localized in the tissue compartment

Fig. 3

Sensitivity analysis of the effect of target concentration on the PK profile of a hypothetical antibody exhibiting TMDD. See text for parameter values used in the simulation