MODELING IN PHARMACODYNAMICS

Neglecting dynamic models in pharmacodynamics [430] is perhaps due to the fact in that instant equilibrium relationships between concentration and effect appear to occur for most drugs. For some drugs, such as cytotoxic agents, this delay is often extremely long, and attempts to model it are seldom made. One can describe these relationships as time-dissociated or nondynamic because the temporal aspects of the effect are not linked to the time-concentration profile. 

Wu B, Joshi A, Ren S, Ng C.The application of mechanism-based PK/PD modeling in pharmacodynamic-based dose selection of muM17 a surrogate monoclonal antibody for Efalizumab. / Pharmaceut Sci 2006 95 1258-68. 

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. 

Sheiner LB, Steimer JL. Pharmacokinetic/pharmacodynamic modeling in drug development. Annu Rev Pharmacol Toxicol 2000 40 67-95. 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

Part 2 Pharmacokinetic/Pharmacodynamic Modeling in New Drug Development... 

Pharmacokinetic/pharmacodynamic model using nonlinear, mixed-effects model in two compartment, best described time course of concentration strong correlation with creatinine clearance predicted concentration at the efi ect site and in reduction of heart rate during atrial fibrillation using population kinetic approach... 

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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