Фармакокинетика и Фармакодинамика (Feb 2018)
The role of studies of interspecies differences pharmacokinetics in the creation of new peptide drugs
Abstract
Resume. The paper presents literature data about the interspecific differences of the pharmacokinetics of peptide drugs and the results of our own studies on the inter-specific features of the pharmacokinetics of the 3 modified analogues of endogenous neuropeptides (noopept, dilept and GB-115) in animals of 2 species (rat, rabbit) and human wich purpose of choosing the optimal extrapolation model for predicting the pharmacokinetics of new peptide drugs in humans by pharmacokinetic parameters. Interspecific differences in the pharmacokinetics of the absorption, metabolism and elimination of dipeptide preparations are established. For the dilept - methyl ester of N-caproyl-L-prolyl-L-tyrosine - dipeptide analogue of the natural neuroleptin neurotensine, using the allometric Dedric method, it was established that the pharmacokinetics in humans can be predicted from a close fit of the pharmacokinetic parameters obtained in animals. For anxiolytic GB-115, the linearity of pharmacokinetic parameters in volunteers is shown in the use of doses in the range 1-15 mg. It is shown that the half-life of the studied peptide compounds in experimental animals is a prognostically significant parameter for extrapolating their pharmacokinetics on humans. In view of the proximity of enzymatic systems in rats and humans, it is advisable to use this species of animals at the stage of studying the pharmacokinetics of the substance of new peptide compounds to obtain general information about their pharmacokinetics and the main metabolic pathways. At the stage of studying the dosage drugs forms of these compounds preference should be given to rabbits as an experimental model, due to the possibility of obtaining the entire pharmacokinetic profile in one animal and calculating individual pharmacokinetic parameters of new peptide drugs.
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