Pharmacodynamics, description

The therapeutic efficacy of a dmg is generally measured in terms of ED q or ID q which represent the concentration of dmg which produces 50% of the maximum effect or 50% of maximum inhibition. LD q represents the concentration of dmg that produces 50% fataUties in test animals. The therapeutic index is the ratio of the ED q versus LD q. Detailed descriptions of the terminology and fundamental principles of pharmacology are available (32) (see Pharmacodynamics). 

The number of subjects per cohort needed for the initial study depends on several factors. If a well established pharmacodynamic measurement is to be used as an endpoint, it should be possible to calculate the number required to demonstrate significant differences from placebo by means of a power calculation based on variances in a previous study using this technique. However, analysis of the study is often limited to descriptive statistics such as mean and standard deviation, or even just recording the number of reports of a particular symptom, so that a formal power calculation is often inappropriate. There must be a balance between the minimum number on which it is reasonable to base decisions about dose escalation and the number of individuals it is reasonable to expose to a NME for the first time. To take the extremes, it is unwise to make decisions about tolerability and pharmacokinetics based on data from one or two subjects, although there are advocates of such a minimalist approach. Conversely, it is not justifiable to administer a single dose level to, say, 50 subjects at this early stage of ED. There is no simple answer to this, but in general the number lies between 6 and 20 subjects. 

Fig. 14. Schematic description of pharmacokinetic and pharmacodynamic determinants of drug action. Distribution from the measurement site (Cp) to the biophase (Ce), determined by a distribution rate constant is followed by drug-induced inhibition or stimulation of the production (k ) or removal (A out) of a mediator (R), transduction of the response R and further transformation of R to the measured effect E, if the measured effect variable is not R. (Modified from Jusko WJ, Ko HC, Ebling WF. Convergence of direct and indirect pharmacodynamic response models. J Pharmacokinet Biopharm 1995 23 5-6.)...

For products in a new pharmacological class where there is no human experience, the pharmacology and pharmacodynamics data will be scrutinized closely by assessors to look for indicators of possible toxicity. Any application should contain a thorough description of the following ... 

For FTIH trials, all applications should include a summary of projected free plasma concentrations of the new active substance (NAS) in humans and a brief description of any pharmacokinetic modelling programs used to generate the estimates. A comparison with the concentrations obtained in the nonclinical toxicity studies and projected safety margins should be given. In the same section, an estimate of the extent of the intended pharmacological or pharmacodynamic response at the expected plasma concentrations should be included, with a list of the assumptions used in deriving that estimate. 

In this case study a simulation strategy, based on a mechanistic PK/PD model, was developed to predict the outcome of the first time in man (FTIM) and proof of concept (POC) study of a new erythropoietin receptor agonist (ERA). A description of the erythropoiesis model, along with the procedures to scale the pharmacokinetics and pharmacodynamics based on preclinical in vivo and in vitro information is presented. The Phase I study design is described and finally the model-based predictions are shown and discussed. 

For the purposes of simplicity, the description of each study is limited to the collection, handling, and interpretation of pharmacokinetic data although clearly safety (and pharmacodynamic) parameters are also studied. 

The secondary analyses consisted of assessing the safety, tolerability and pharmacodynamic responses after administration of XYZ1234 and XYZ1234 in plasma and urine using descriptive statistics. 

While formulation interactions often are subject to in vitro investigations, the section below presents a particular example of an in vivo formulation interaction study (CPMP/EWP/QWP/1401/98 2002) a potential interaction of a drug in medical practice frequently given concomitantly with another drug (i.e. both mixed in a syringe) was subject to a clinical study which is illustrated below. For the purposes of simplicity, the description is limited to the collection, handling, and interpretation of pharmacokinetic data although clearly safety and pharmacodynamic parameters were also studied. 

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