Preclinical Pharmacokinetics

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

T. E., Silber, M., Jones, B. C., MacIntyre, F., Rance, D. J., Wastall, P., The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data, J. Pharmacol. Exp. Ther. 1997,... 

Relatively high molecular weight is a feature of the chemotype exemplified by 4-11 and this can require creative formulation techniques. Pharmacokinetic properties of a lead candidate (structure unknown) from the same series that provided 10 were inadequate to provide sufficient exposures at high doses to support preclinical safety studies. However, cocrystal formulations with saccharin or gentisic acid improved water solubility by 50-fold and increased oral exposures up to 10-fold relative to traditional formulations at 20mg/kg [64]. 

Incorporation of fluorine at a site adjacent to a "metabolic soft spot" has also been used as a strategy to increase duration of action. Linopir-dine (24) was among the first clinical compounds that enhanced potassium-evoked release of acetylcholine in preclinical models of AD [22]. Linopirdine showed no clinical efficacy and its human pharmacokinetic profile was suggested as the reason for this lack of clinical efficacy. Specifically noted was the molecule s poor brain exposure and short half-life due to formation of the N-oxides 25 and 26 (Table 3) [23,24]. Optimization of 24 resulted in replacement of the indolone core by the anthracenone 27, which had improved in vitro activity, but still exhibited a short duration of action. To improve the metabolic stability, fluorine... 

During preclinical assessment of an enantiometric mixture, it may be important to determine to which of these three classes it belongs. The pharmacological and toxicological properties of the individual isomers should be characterized. The pharmacokinetic profile of each isomer should be characterized in animal models with regard to disposition and interconversion. It is not at all unusual for each enantiomer to have a completely different pharmacokinetic behavior. 

Tse, F.L.S. and Jaffe, J.M. (1991). Preclinical Drug Disposition. Marcel Dekker, New York. Vinegar, A. and Jepson, G. (1996). Cardiac sensitization thresholds of halon replacement chemicals in humans by physiologically based pharmacokinetic modeling. Risk Analysis 16 571-579. 

Overall, trifluorophenyl analogue 1 was superior to all triazolopiperazine derivatives with respect to DPP-4 potency, off-target selectivity, pharmacokinetic profile and in vivo efficacy in preclinical species and was selected for further development. In vitro potency and selectivity of compound 1 (sitagliptin) are illustrated in Table 17.8. Sitagliptin is a very selective D P P-4 inhibitor, showing 2700-fold selectivity over D P P-8 and more than 5000-fold selectivity over other DASH proteins. Sitagliptin was further profiled in an extensive panel of over 170 enzymes, receptors and ion... 

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