who constructed a PBPK model for the CC49 mAb to predict not only its biodistribution in various tissues but also in the tumor compartment which was the intended site of action (21). 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 generatedin vitroandin vivo, predict human PKPD, and provide a rationalized approach to designing the first-in-human study. Key words:biologics, drug discovery, modeling and simulations, pharmacodynamics, pharmacokinetics == INTRODUCTION == The growth of biopharmaceuticals (BPs) over the last 20 years has indeed been nothing short of amazing. In late-stage development, by 2006, there were 111 unique BPs for 190 indications in 38 disease categories (1). In 2009 2009, four monoclonal antibodies (mAbs) gained FDA approval, the highest annual number in over a decade (2). In 2010 2010, of the 21 molecular entities that gained approval, six were biologics (3). By the same 12 months, a total of more than 20 therapeutic antibodies were approved and more than 200 were in development (4). The rise in the proportion of biologics to small-molecule approvals may well be attributed to the introduction of technologies that have enabled the engineering of a wide range of targeted biological modalities. In addition to mAbs, antisense oligonucleotides, therapeutic genes, recombinant and DNA vaccines, and antibodydrug conjugates are expanding the industry-wide BP pipeline (5,6). As BPs are growing in complexity in terms of their structures and mechanisms of action, so are interpretation, analysis, and prediction of their pharmacokinetic (PK) and pharmacodynamic (PD) properties, collectively, pharmacokineticpharmacodynamic (PKPD). Unlike what is typically seen for small-molecule compounds, the PK of BPs can be significantly affected by the PD,i.e., target kinetics, abundance, affinity, and depletion or accumulation, etc. Those confounding variables necessitate mechanistic models to describe their PKPD properties. For example, beyond phenomenological models, systems biology (SB) and systems pharmacology (SP) models may be needed to describe and predict their behavior. Undoubtedly, the use of model-based analysis from early discovery leading to the 4-Butylresorcinol design of the first-in-human (FIH) study is crucial for rationalized decision making during the drug discovery and development process. Thus, data and mechanistic information collected from variousin vitroandin vivoexperiments at all stages of preclinical development can, and perhaps should be, compiled into an integrative and quantitative framework. PKPD and SB/SP, collectively modeling and simulation (M&S), is usually arguably the best available tool to achieve this goal. The objective of this manuscript is usually to present an introductory overview of a model-based 4-Butylresorcinol framework for the successful preclinical development of mAbs (as an illustrative example of BPs) and discuss M&S strategies for its implementation. For the purpose of this manuscript, the Rabbit Polyclonal to SUCNR1 term preclinical includes early discovery 4-Butylresorcinol stages leading to the design of the FIH study. For simplicity, our use of the term biopharmaceuticals may be synonymous with others such as biologics and biotherapeutics. == A M&S FRAMEWORK FOR PRECLINICAL DEVELOPMENT OF mAbs == Depicted in Fig.1is an integrated framework for model-based drug discovery for mAbs. The actions in the diagrams are meant to be taken in a continuum rather than strongly demarcated, since knowledge and model building would naturally progress as new data are collected along the R&D process with time. In early discovery,bona fideSB approaches may be used to reconstruct the molecular pathway of the target and aid the understanding of the target biology, in addition to supporting target identification, validation, and selection. This is also a stage at which building 4-Butylresorcinol a physiologically based PK (PBPK) model could begin in conjunction with target system or pathway models to improve the understanding of mAb distribution, especially if tissue localization of the target is usually important. == Fig. 1. == Summary of the model-based preclinical development framework for biopharmaceuticals.Boxes with dotted linesrepresent modeling and simulation specific activities ideally implemented during preclinical development During lead optimization, SP, which, for the 4-Butylresorcinol purpose of this framework, may include mechanistic PKPD,.
