Pharmacological differences between pharmacodynamics

Bioequivalence and -avalibility can be assessed in vitro, for example in dissolution tests for controlled release forms, or in vivo in experimental animals in pharmacokinetic and/or pharmacodynamic studies. The results should be correlated with the pharmacological effects in the target organism. If the modified product is not bioequivalent or shows different therapeutic effects, clinical studies will be necessary. Products which have a narrow therapeutic ratio (e.g. a less than twofold difference between the minimum toxic and minimum effective concentration in the body 21 CFR 320) require clinical studies under all circumstances. 

Similarity/differences between enantiomers Pharmacodynamics (pharmacology and toxicity) Metabolic disposition... 

Drayer, D.E. (1986) Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans an overview. Clinical Pharmacology and Therapeutics, 40, 125-133. 

As the compound reaches the late discovery and candidate selection stage, the focus is to determine its major metabolic pathways, metabolic difference between species, and to identify potential pharmacologically active or toxic metabolites. Because of the complexity, comprehensive metabolite characterization studies have been typically conducted at this stage with radiolabeled standard. Identification of circulating metabolites is also important at this stage to explain the pharmacokinetic or the pharmacodynamic profile. An NCE may show efficacy that is inconsistent with what is predicted based upon the known concentration of the parent drug. These inconsistencies could be due to the presence of active metabolites. The knowledge of these metabolites will also dictate how the analysis of samples will be conducted in the development and clinical studies. 

The most important differences between enantiomers occur in drug receptor interactions. Indeed, Lehmann [34] has stated, the stereoselectivity displayed by pharmacological systems constitutes the best evidence that receptors exist and that they incorporate concrete molecular entities as integral components of their active-sites. In contrast to the pharmacokinetic properties of a pair of enantiomers (Sec. 4), differences in pharmacodynamic activity tend to be more marked, and eudismic ratios of 100 to 1000 are not uncommon. 

S Dose levels in vivo It is necessary to define the dose-response relationship of any adverse effects observed. The onset and duration of effects should be measured. Because there are differences in sensitivity between species, the doses chosen need to exceed those used for therapy. The ICH guideline states that the highest dose tested should be a dose that produces moderate adverse effects, for example, dose-limiting pharmacodynamic effects or other toxicities. Such effects should not be so severe that they confoimd the interpretation of the results being sought. Safety pharmacology studies... 

Pharmacodynamics, antipsychotics also differ in their pharmacodynamics, i.e. their pharmacological and clinical profiles of action. A rough distinction is made between highly sedative, hypnotic antipsychotics (e.g. clopenthixol, levomepromazine) and other products with weaker initial sedative action (e.g. fluphenazine and haloperidol). Sedative antipsychotics are prescribed for states of major unrest, often combined with insomnia, whereas the less sedative antipsychotics are preferred for patients suffering from delusions and hallucinations but in whom heavy sedation during daytime is undesirable. 

Smith, B.J., Doran, A.C., Mclean, S., Tingley, F.D., III, O Neil, C.A. and Kajiji, S.M. (2001) P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists. Journal of Pharmacology and Experimental Therapeutics, 298, 1252—1259. 

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