Elementary Aspects

The possibility that time since lose changes the relationship between pharmacological effect size

and drug concentrations in plasma has been known for a long time (Levy 1964, 1966; Levy and Nelson 1965; Wagner 1968; Curry 1980). The pioneering work was done by Levy and his colleagues in the 1960s on single dose-plasma level-effect relationships, and on the duration of action of drugs as a function of dose. Brodie and colleagues had shown even earlier how complicated the relationships are when drugs with multicompartment distribution are studied in this context (e.g. Brodie 1967). Lasagna and colleagues, using diuretics, found that depending on whether a cumulative effect (24 h urine production) or an 'instant' effect (rate of urine flow at a particular time) were measured, different relationships of response were possible (Murphy et al 1961). Nagashima et al (1969) demonstrated the relative time courses of anticoagulant concentration and effect. Thus, the relationship between effect size and concentration of drug in plasma should not be expected to be constant or simple, and can vary with time.

The objectives of modern analysis of drug action are to delineate the chemical or physical interactions between drug and target cell and to characterize the full sequence and scope of actions of each drug (Ross 1996). Preclinical models describing the relationship between the concentration of drug in blood or plasma, and drug receptor occupancy or functional response, provide clinically useful tools regarding potency, efficacy, and the time course of effect.

Potency is an expression of the activity of a compound, in terms of either the concentration or amount needed to produce a defined effect. Emax is the maximal drug-induced effect. EC50 is the concentration of an agonist that produces 50% of the maximal possible response. An EC50 can be described for drug concentrations using in vitro assays, or as a plasma concentration in vivo. IC50 is the concentration of an antagonist that reduces a specified response to 50% of its former value.

A measure of the tendency of a ligand and its receptor to bind to each other is expressed as Kd in receptor occupancy studies. Kd is the equitibrune contant for the two processes of drug-receptor combination and dissociation. Kd may be found for both agonists and antagonists, although sometimes the former poses more technical challenge, due to alterations to the conformation of the binding site. In contrast, efficacy is a relative measure, amongst different agonists, describing response size for a standard degree of receptor occupation (Jenkinson et al 1995). When an agonist must occupy 100% of available receptors to cause Emax, its efficacy may be said to be unity. If occupation of all receptors achieves a response that is less than Emax, then the agonist's efficacy is less than one, and equal to the ratio of observed maximal effect/ maximal effect for an agonist with efficacy = 1 (we call these partial agonists or agonist-antagonists). Some agonists need occupy only a subset of the available receptors, in order to achieve Emax, and these have efficacy greater than unity. In the latter case, the concentration-response curve lies to the left of the concentration-receptor occupancy curve (e.g. Minneman et al 1983). Drugs with efficacy > 1 are also called full agonists.

Below, we present some model relationships between observed concentration and effect size, as examples from a considerable volume of literature. The reader is referred to key texts for comprehensive coverage of this topic (e.g. Smolen 1971; Gibaldi and Perrier 1982, Dayneka et al 1993; Levy 1993; Lesko and Williams 1994; Colburn 1995; Derendorf and Hochhaus 1995; Gabrielsson and Weiner 1997; Sharma and Jusko 1997).

0 0

Post a comment