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

Abstract

Objectives: 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.

Methods: Two (2S,3S)-SPD intramuscular formulations (F_A and F_B ) were administered to pigs and rats and blood samples were withdrawn at different times after dosing.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.

Results: In rats, (2S,3S)-SPD plasma exposure increased proportionally following intramuscular dosing (20, 25 and 40 mg/kg) of F_A and F_B . Peak plasma concentration (C_max ) was obtained at 1-2 hours after dosing and ranged between 6.8 and 9.4 mg/L. (2S,3S)-SPD plasma concentration at 10 minutes after dosing (C₁₀ ) ranged between 2.1 and 3.5 mg/mL, and its half-life ranged between 0.9 and 2.3 hours. The highest C₁₀ value, which may indicate rapid activity onset, and the highest C_max were observed following administration of F_A (40 mg/kg): C₁₀ = 3.5 mg/L and C_max = 9.5 mg/L. In the MEST test, (2S,3S)-SPD (20 and 60 mg/kg) significantly raised the tonic seizure threshold compared to vehicle at 4, 7, 10, and 20 minutes after dosing, with a 1.6-fold increase at 20 minutes, which coincided with (2S,3S)-SPD brain C_max . Following intramuscular dosing of (2S,3S)-SPD (12 mg/kg) to pigs of F_A and F_B , a C_max value of 0.9 mg/L was obtained 0.42 and 0.75 hours after dosing, respectively. (2S,3S)-SPD C₁₀ was 0.27 mg/L (F_A ) and 0.49 mg/L (F_B ). (2S,3S)-SPD clearance, volume of distribution, and half-life were 2 L/h/kg, 18-28 L/kg, and 6.1-9.7 hours, respectively.

Significance: (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 >12 mg/kg are required to achieve in pigs the plasma concentrations associated with activity at the rat MEST test.

Keywords: (2S,3S)-sec-butylpropylacetamide (SPD); CNS-active amide derivatives of valproic acid; PK-PD correlation; an individual stereoisomer of SPD; maximal-electroshock seizure threshold (MEST) model.