Concentration-effect relationships

Webster, R., Leischmann, D., and Walker, D., Towards a drug concentration effect relationship for QT prolongation and torsades de pointes, Curr. Opin. Drug Discov. Dev., 5,116-126, 2002. 

A fundamental experiment that characterizes the function of an expressed receptor is to determine the concentration-effect relationship. By measuring the response of the receptor population to a range of drug concentrations, the potency of a drug can be determined (e.g., O Figure 14-2). In these experiments, an... 

The effectiveness of drug targeting should be evaluated by taking into account not only pharmacokinetic aspects, but also the pharmacodynamic aspects. The latter include the concentration-effect relationship in the target tissue and at the sites where toxicity may occur [7,12]. The therapeutic effect of the drug and its toxic effect may be different with regard to their mechanisms, and hence their concentration-effect relationship may also be different, both qualitatively (different PD models) and quantitatively (different model parameters). 

For simplicity, a linear relationship between concentration and effect is often assumed, reducing the problem of PK/PD to the pharmacokinetics. However, the concentration-effect relationship of any drug tends towards a plateau, and a sigmoidal model (sigmoid E ax model or Hill equation) is more appropriate [21-24] ... 

As the concentration is raised by a constant factor, the increment in effect diminishes steadily and tends asymptotically towards zero the closer one comes to the maximally effective concentra-tion.The concentration at which a maximal effect occurs cannot be measured accurately however, that eliciting a half-maximal effect (EC50) is readily determined. it typically corresponds to the inflection point of the concentration-response curve in a semilogarith-mic plot (log concentration on abscissa). Full characterization of a concentration-effect relationship requires determination of the EC50. the maximally possible effect (Emax), and the slope at the point of inflection. 

The time course of the effect and of the concentration in plasma are not identical, because the concentration-effect relationships obeys a hyperbolic function (B cf. also p. 54). This means that the time course of the effect exhibits dose dependence also in the presence of dose-linear kinetics (C). 

Related terms Effect Assessment, Dose-Response Relationship, Concentration-Effect Relationship. 

Related terms Dose—Effect Relationship, Effect Assessment, Concentration—Effect Relationship. 

Other terms often used indiscriminately for the dose-response relationship include concentration-effect relationship and dose-effect relationship. According to the joint OECD/IPCS project (OECD 2003 a), which has developed internationally harmonized generic and technical terms used in chemical hazard and risk assessment, the following definitions have been provided although consensus was not achieved ... 

Dose levels in vitro As for in vivo studies, it is necessary to establish a concentration-effect relationship. The upper limit of concentrations tested may be influenced by physicochemical properties of the test substance and other factors such as cytotoxicity. 

In addition to toxicity and safety data, the preclini-cal package to start clinical studies also contains information on the pharmacology, the pharmacokinetics and metabolism and the galenical aspects of the compound. As a rule there is evidence of pharmacological activity and, if possible, of therapeutic activity in one or more animal models of disease. Ideally there is also information on the in vivo concentration effect relationship. 

Ternant D, Paintaud G. Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins. Expert Opin Biol Ther 2005 Suppl 1 837-47. 

Primary model selection should be based on the experimental data observations but other Information may also be useful, such as knowledge of the drug s mechanism of action, results from earlier studies, or concentration-effect relationships of related compounds. The performance of different models can be systematically tested by using a nonlinear regression program, which has readymade routines for common models and also allows the user to formulate his own models. Model selection and validation Is an Important Issue, which Is however beyond the scope of this chapter. 

Fig. 3. Concentration-effect relationship for the sigmoid Emax model with 5 = 0.5, 1, 3 and 5, respectively, (a) Linear concentration scale, (b) logarithmic concentration scale.

Fig. 6. Counterclockwise hysteresis appearing between hearing threshold shift and quinine plasma concentration in a subject who received two identical oral doses (dotted and solid lines) and an infusion (dashed line) of quinine. (From Paintaud G, Alvan G, Beminger E et al. The concentration-effect relationship of quinine-induced hearing impairment. Clin Pharmacol Ther 1994 55 317-23, with permission from MOSBY Inc.)...

There may be several reasons for this pattern to be observed. One obvious reason is distribution, i.e. the drug needs time to reach its site of action, and the time lag between the measured drug concentration in plasma and the drug effect is due to distributional delay. In order to describe such a plasma concentration-effect relationship, a PK-PD model that allows for drug distribution to the site of action, e.g. the effect compartment model may be used. 

Bell shaped concentration-effect relationships (an Emax curve, followed by a decrease in effect when concentrations are further increased) have been observed for a number of drugs. Concerning serotonin 5-HT3 receptor antagonists, a decrease in effect was reported with increasing doses of tropisetron and dolasetron. This implies a bell shaped concentration-effect relationship, which may be due to the fact... 

The concentration-effect relationship of qninine-induced hearing impairment. Clin Pharmacol Ther... 

Comprehensive knowledge of the clinical pharmacology (e.g., concentration-effect relationships, pharmacokinetic and pharmacodynamic profile, information related to altered drug disposition and/or action consequent to development, disease, concomitant drug therapy) for the drug(s) of interest... 

Figure 5.8. Concentration-effect relationship. A representative curve demonstrating the effects observed with increasing drug concentration, typ-icaiiy measured in piasma and expressed as an average and varied among individuais. Drug concentrations are piotted on a iog scaie. Maximum effect is achieved when no additionai effect intensity can be obtained with increasing drug concentration. A simiiar reiationship can be expressed as a function of dose administered to subjects, in this case the piot is caiied dose-effect or dose-response curve.

Dall Ozzo S, Tartas S, Paintaud G et al. Rituximab-dependent cytotoxicity by natural killer cells influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res 2004 64 4664 669. 

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