Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies
Journal Title: The AAPS Journal - Year 2013, Vol 15, Issue 2
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 and Affiliations
Kenneth T. Luu, Eugenia Kraynov, Bing Kuang, Paolo Vicini, Wei-Zhu Zhong
Keywords
Related Articles
- EP ID EP681116
- DOI 10.1208/s12248-013-9464-8
- Views 66
- Downloads 0
“Fit-for-Purpose” Method Validation and Application of a Biomarker (C-terminal Telopeptides of Type 1 Collagen) in Denosumab Clinical Studies
Biomarkers are used to study drug effects, exposure–response relationships, and facilitate early decision making during development. Denosumab, a fully human monoclonal antibody against receptor activator of nucl...
Drug Discovery and Regulatory Considerations for Improving In Silico and In Vitro Predictions that Use Caco-2 as a Surrogate for Human Intestinal Permeability Measurements
There is a growing need for highly accurate in silico and in vitro predictive models to facilitate drug discovery and development. Results from in vitro permeation studies across the Caco-2 cell monolayer are commonly us...
Species and Gender Differences Affect the Metabolism of Emodin via Glucuronidation
The aim of the present study was to define the mechanisms responsible for poor bioavailability of emodin by determining its metabolism using in vitro and in situ disposition models of the intestine and liver. Liver micro...
Simultaneous population optimal design for pharmacokinetic-pharmacodynamic experiments
Multiple outputs or measurement types are commonly gathered in biological experiments. Often, these experiments are expensive (such as clinical drug trials) or require careful design to achieve the desired information co...
On some “disadvantages” of the population approach
In a seminal article on population pharmacokinetic modeling, researchers demonstrated how means and variances of pharmacokinetic parameters for a patient population could be inferred from sparse data collected under cond...