Drug activity phases pharmacodynamic phase

When using QSAR calculations to optimize a drug for the pharmacodynamic phase, it is important to use relevant biological activities. If in vivo activities are used, the bioactivities will be influenced by pharmacokinetic and pharmaceutical factors. In order for QSAR calculations to reflect the pharmacodynamic phase, the bioactivities should be based on in vitro data — optimally, receptor binding studies. 

QSAR studies are not restricted to the optimization of biological activity at the pharmacodynamic phase. Since toxicity also arises from drug-receptor interactions, the QSAR... 

Phase I studies involve some combination of the evaluation of initial safety and tolerability, pharmacokinetics, pharmacodynamics, and an early measurement of drug activity. The initial clinical study is typically a single dose study conducted in normal healthy volunteers. The initial dose in the study is estimated from the nonclinical data and this dose is escalated until adverse events are seen. This study results in the determination of the maximally tolerated dose of the drug. Analysis of pharmacokinetic parameters and relation of blood levels to adverse events gives great insight for future studies. 

Pharmacodynamic phase Quality of the drug-receptor interaction Nature and intensity of the biological response Maximal activity Maximal selectivity Minimal toxicity... 

The cl mg discovery process can be envisioned as four interconnected phases (see Figure 8.1). Generally, these are the acquisition of chemicals to be tested for biological activity, the determination of the activity of those chemicals on biological systems (pharmacodynamics), the formulation of the most active of these for therapeutic testing in humans (pharmaceutics), and the determination of adequate delivery of the active drug to diseased tissues (pharmacokinetics). Each of these collections of processes is interconnected with the others and failure in any one of them can halt the development process. It is worth considering each process separately, as well as the relationships between them. 

Human pharmacology (Phase I) Assess tolerance Define/describe pharmacokinetics and pharmacodynamics Explore drug metabolism and drug interactions Estimate activity Dose-tolerance studies Single and multiple dose PK and/or PD studies Drug interaction studies... 

Many types of modeling techniques are available in the discovery phase of drug development, from structure activity relationships (SAR) to physiology based pharmacokinetics (PBPK) and pharmacokinetics-/pharmacodynamics (PK/PD) to help choosing some of the lead compounds. Some tests that are carried out by discovery include techniques related to structure determination, metabolism, and permeability NMR, MS/MS, elemental analysis, PAMPA, CACO-2, and in vitro metabolic stability. Although they are important as a part of physicochemical molecular characterization under the biopharmaceutics umbrella, they will not be discussed here. The reader can find relevant information in numerous monographs [9,10]. 

C. P. (2006). First-in-human experience of an antidote-controUed anticoagulant using RNA aptamer technology a phase la pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation 114, 2490-2497. 

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