Pharmacokinetic and pharmacodynamic analysis of (2S,3S)-sec-butylpropylacetamide (SPD) in rats and pigs-A CNS-active stereoisomer of SPD.

Abstract

To advance the development of (2S,3S)-sec-butylpropylacetamide (SPD) as a new treatment for acute repetitive seizures (ARS), by studying its pharmacokinetics (PK) in pigs and its PK-pharmacodynamic (PK-PD) correlation in rats. Two (2S,3S)-SPD intramuscular formulations (FA and FB ) were administered to pigs and rats and blood samples were withdrawn at different times after dosing. Major PK parameters were estimated in both species. PD analysis was conducted in rats utilizing the maximal-electroshock seizure threshold (MEST) test. Because ARS treatment requires a rapid action, the MEST test allows comparative evaluation of (2S,3S)-SPD intramuscular injection on rat susceptibility to electroconvulsive shock at various times after dosing. In rats, (2S,3S)-SPD plasma exposure increased proportionally following intramuscular dosing (20, 25 and 40mg/kg) of FA and FB . Peak plasma concentration (Cmax ) was obtained at 1-2hours after dosing and ranged between 6.8 and 9.4mg/L. (2S,3S)-SPD plasma concentration at 10minutes after dosing (C10 ) ranged between 2.1 and 3.5mg/mL, and its half-life ranged between 0.9 and 2.3hours. The highest C10 value, which may indicate rapid activity onset, and the highest Cmax were observed following administration of FA (40mg/kg): C10 =3.5mg/L and Cmax =9.5mg/L. In the MEST test, (2S,3S)-SPD (20 and 60mg/kg) significantly raised the tonic seizure threshold compared to vehicle at 4, 7, 10, and 20minutes after dosing, with a 1.6-fold increase at 20minutes, which coincided with (2S,3S)-SPD brain Cmax . Following intramuscular dosing of (2S,3S)-SPD (12mg/kg) to pigs of FA and FB , a Cmax value of 0.9mg/L was obtained 0.42 and 0.75hours after dosing, respectively. (2S,3S)-SPD C10 was 0.27mg/L (FA ) and 0.49mg/L (FB ). (2S,3S)-SPD clearance, volume of distribution, and half-life were 2L/h/kg, 18-28L/kg, and 6.1-9.7hours, respectively. (2S,3S)-SPD demonstrated a good PK-PD correlation in the rat MEST test, with a rapid onset. (2S,3S)-SPD first PK study in pigs showed that doses >12mg/kg are required to achieve in pigs the plasma concentrations associated with activity at the rat MEST test.