title: 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.
authors: Department of Clinical Pharmacology, Pfizer Global Research and Development, 10555 Science Center Drive, San Diego, CA 92121, USA. kenneth.luu@pfizer.com
authors: Kenneth T
authors: KT
authors: Luu
authors: Eugenia
authors: E
authors: Kraynov
authors: Bing
authors: B
authors: Kuang
authors: Paolo
authors: P
authors: Vicini
authors: Wei-Zhu
authors: WZ
authors: Zhong
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003198:Computer Simulation; D003661:Decision Support Techniques; D004195:Disease Models, Animal; D054796:Drug Dosage Calculations; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008954:Models, Biological; D017711:Nonlinear Dynamics; D049490:Systems Biology; D057170:Translational Research, Biomedical / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal