Dose-concentration-effect relationship

The dose-concentration-effect relationship is defined by the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of a drug. Pharmacokinetics comprises all processes that contribute to the time course of drug concentrations... 

The earliest attempts to characterize the PK/PD (dose-concentration-effect) relationships were mostly limited to those drngs with direct correlation between observed effect and measnred concentrations. ... 

Regardless of the techniques used, the goals should be to characterize the pharmacokinetics in the patient population, and to quantify the dose-concentration-effect relationship. Phase Ila studies allow the first characterization of pharmacokinetics in patients, but opportunities for pharmacodynamic evalnation or phar-macokinetic/pharmacodynamic modeling may be more limited than in Phase 11b. With Phase Ilb data over several doses, it may be possible to define this relationship, or at least obtain estimates of the lowest useful concentration and the concentration beyond which additional response is not anticipated. Since Phase 11 patient popnla-tions tend to be larger and more diverse than the healthy volunteers nsed in Phase I studies, there are further opportunities to help identify sources of interindividual variability in pharmacokinetics and pharmacodynamics. 

Doses selected for safety pharmacology studies are typically based on the criteria established in the ICH S7A guidance.25 Doses should exceed those projected for clinical efficacy and at the upper limit be bound by (1) adverse pharmacodynamic effects in the safety pharmacology study (2) moderately adverse effects in other non-clinical studies that follow a similar route and duration of dosing or (3) limit of solubility/toxicity. In the absence of adverse effects, the maximum administrable dose can be used. If nonreusable animals enter the study, then the maximum tolerated dose may be appropriate. Most importantly, the doses/concentrations should establish the dose/concentration-response relationship of the adverse effect. 

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. 

The first and subsequent studies of a NME in humans should aim to obtain dose-concentration-response relationships for desired and undesired effects. These objectives may be summarised as follows ... 

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.)...

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... 

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.

Fig. 15.10 Concentration-effect relationship of pegfilgrastim based on a simple Emax model. The average concentrations of pegfilgrastim from patients with breast cancer at doses of 30, 60, and 100 pg/kg are indicated ( ).

The effects are statistically significant and show an unambiguous concentration-effect relationship, or the observed effects are in agreement with a dose-effect relationship from additional studies. 

What could be done to better assess immunomodulatory effects in NHP that will be predictive of the outcome in humans One important consideration comes back to the relevance of the animal species. Not only should the binding affinity and functionality at the target be considered, but the relative potency as well can be a critical factor. Understanding the dose-concentration-response relationships for receptor occupancy, receptor modulation and functionality, and target expression and distribution in comparison to normal human subjects and in disease state can help us to better assess risk to patients. 

The methods described here are applied for Supplemental Safety Pharmacology Studies (ICH S7A), if the test substance has shown indications of effects on the hypothalamic-pituitary-adrenal system in the preceding pharmacology studies. The in vitro studies are generally performed with several increasing doses to investigate concentration-effect relationships. The preliminary information from these in vitro studies is then compared with the biological information available from in vivo for studies, to assess the need for additional animal studies based on repeated dose administration of the test compound. 

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