Drug activity phases pharmacokinetic phase

We thus have a series of unbound drug affinity measures relating to the action of the drug. The values are those typically obtained by the pharmacologist and form the basis of the structure-activity relationships which the medicinal chemist will work on. It is possible to extend this model to provide a pharmacokinetic phase as shown in Figure 2.9. 

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. 

The pharmacokinetic phase of drug action includes the Absorption, Distribution, Metabolism and Elimination (ADME) of the drug. Many of the factors that influence drug action apply to all aspects of the pharmacokinetic phase. Solubility (see Section 3.3), for example, is an important factor in the absorption, distribution and elimination of a drug. Furthermore, the rate of drug dissolution, that is, the rate at which a solid drug dissolves in the aqueous medium, controls its activity when a solid drug is administered by enteral routes (see Section 2.6) as a solid or suspension. 

He took over the responsibility for the complete Drug Metabolism and Pharmacokinetics Department in Frankfurt in 2000. His activities ranged from in-silico approaches at very early stages of the value chain, in-vitro studies, and in vivo animal studies up to Phase I, II and III clinical studies. The whole scope of these activities... 

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. 

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. 

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