Preclinical and Clinical Pharmacokinetics of a Novel Dipeptide Anxiolytic GB-115

[Speaker] Pavel O Bochkov:1
[Co-author] Larisa G Kolik:1, Vladimir P Zherdev:1, Gennadiy B Kolyvanov:1, Alexander A Litvin:1, Sergei Yu Raskin:1, Roman V Shevchenko:1, Oxana G Grybakina:1, Tatiana A Gudasheva:1, Sergei B Seredenin:1
1:FSBI, Russia

Background. A novel dipeptide GB-115, designed and synthesized in the "Zakusov Research Institute of Pharmacology", as an analogue of endogenous cholecystokinin-4, produced pronounced anxiolytic properties in different rodent models without adverse effects typical to benzodiazepines. Based on preclinical pharmacodynamic/pharmacokinetic results for clinical studies was recommended a tablet formulation. The aim of this study was to evaluate GB-115 pharmacokinetics in rats, rabbits and volunteers.
Methods. GB-115 - C6H5-(CH2)5CO-Gly-Trp-NH2 is dipeptide anxiolytic. Quantification of GB-115 in the rat, rabbit and human blood plasma carried out by HPLC-MS/MS. Substance of GB-115 administered as a single oral dose (100 mg/kg) in rats, GB-115 tablet administered as a single oral dose (30 mg/kg) in rabbits. Anxiolytics pharmacokinetics was studied in healthy volunteers after single oral administration of 15 mg tablets.
Results. The dipeptide drug administered per os enters the rat brain. Relative bioavailability of GB-115 (tablets) in comparison to substance was 128.18+/-36.07% in rabbits. The GB-115 half-lifes in the real (chronological; t1/2el) and the corrected (pharmacokinetic; t1/2 el pk) times were calculated. The value of GB-115 t1/2el in rats obtained on the basis of the averaged pharmacokinetic profile was 0.2 h, while after transformation the t1/2 el pk value was increased to 0.6 h. For rabbits was observed inverse relationship, the mean t1/2el value calculated for the real time was equaled 1.3+/-0.3 h and after correction on "pharmacokinetic" time was 0.9+/-0.2 h. Using the allometric approach the forecast GB-115 t1/2el in humans was calculated in the range of 0.9 to 1.3 h. Pharmacokinetics after administration of GB-115 tablets was studied in volunteers and calculated the half-life of drug that was 1.0+/-0.2 h. Thereby, interspecies differences were found in GB-115 pharmacokinetics: elimination rate constant was decreased in order rat>human>rabbit, by contrast the half-life of GB-115 was increased in order rat<human<rabbit.
Conclusion. High relative bioavailability of the developed GB-115 (tablet) indicates the prospects of its application in medical practice. Based on the interspecies transfer the calculation of the half-life of GB-115 in humans corresponded to t1/2el obtained from volunteers.
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