Pharmacodynamics, systems models

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based dose-response model which quantitatively describes the relationship between target tissue dose and toxic end points. These models advance the importance of physiologically based models in that they clearly describe the biological effect (response) produced by the system following exposure to an exogenous substance. 

Holford NHG. Physiological alternatives to the effect compartment model. In D Argenio DZ, editor. Advanced methods of pharmacokinetic and pharmacodynamic systems analysis. New York Plenum Press 1991. p.55-68. 

J. Mandema, D. Verotta, and L. B. Sheiner, Building population pharmacokinetic-pharmacodynamic models, in Advanced Pharmacokinetic and Pharmacodynamic Systems Analysis, D. Z. D Argenio (Ed.). Plenum Press, New York, 1995, pp. 69-86. 

Nestorov, I. A. (1999). Sensitivity analysis of [4iarmacokinetic and pharmacodynamic systems 1. A structural approach to sensitivity analysis of physiologically based pharmacokinetic models. J Pharmacokinet Biopharm 27, 577-596. 

The consequence of moving consciously toward this model will be the provision of a robust and scalable IT infrastructure and systems able to cope with exponentially growing data mountains that will need to be integrated and shared, accessed and mined in the most effective way. It will also require formidable computing power and sophisticated algorithms to be able to simulate both organs and whole body systems to reduce expensive failures in the clinic and predict much earlier the pharmacokinetic and pharmacodynamic properties and toxicological and efficacy profiles of molecules in pharmaceu-... 

Mager, D.E. and Jusko, W.J., Pharmacodynamic modeling of time-dependent transduction systems, Clin. Pharmacol. Ther., 70, 210-216, 2001. 

Pharmaceutical firms have to reexamine their strategies to devise means to increase their drug pipelines for continuous streams of products. The high failure rates of Investigational New Drugs during clinical trials (see Exhibit 5.8) necessitate the development of better assay systems and animal models that correlate closely with human pharmacodynamics and pharmacokinetics. The study of pharmacogenomics will be crucial to address this issue. 

RNAi has had an important impact on the development of novel disease models in animals, and it is likely that siRNAs, the trigger molecules for RNA silencing, will become an invaluable tool for the treatment of genetic disorders. The rational design of siRNAs, the introduction of chemical modifications into siRNAs to improve their pharmacokinetic and pharmacodynamic properties for in vivo application with high specificity, and the development of efficient delivery system will foster the therapeutic application of RNAi in AD and other neurodegenerative disorders (413,417). 

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