{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T01:05:58Z","timestamp":1747184758420,"version":"3.40.5"},"reference-count":36,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,1,20]],"date-time":"2020-01-20T00:00:00Z","timestamp":1579478400000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To advance the development of (2S,3S)\u2010<jats:italic>sec<\/jats:italic>\u2010butylpropylacetamide (SPD) as a new treatment for acute repetitive seizures (ARS), by studying its pharmacokinetics (PK) in pigs and its PK\u2010pharmacodynamic (PK\u2010PD) correlation in rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two (2S,3S)\u2010SPD intramuscular formulations (F<jats:sub>A<\/jats:sub> and F<jats:sub>B<\/jats:sub>) were administered to pigs and rats and blood samples were withdrawn at different times after dosing.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\u2010electroshock seizure threshold (MEST) test. Because ARS treatment requires a rapid action, the MEST test allows comparative evaluation of (2S,3S)\u2010SPD intramuscular injection on rat susceptibility to electroconvulsive shock at various times after dosing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In rats, (2S,3S)\u2010SPD plasma exposure increased proportionally following intramuscular dosing (20, 25 and 40\u00a0mg\/kg) of F<jats:sub>A<\/jats:sub> and F<jats:sub>B<\/jats:sub>. Peak plasma concentration (C<jats:sub>max<\/jats:sub>) was obtained at 1\u20102\u00a0hours after dosing and ranged between 6.8 and 9.4\u00a0mg\/L. (2S,3S)\u2010SPD plasma concentration at 10\u00a0minutes after dosing (C<jats:sub>10<\/jats:sub>) ranged between 2.1 and 3.5\u00a0mg\/mL, and its half\u2010life ranged between 0.9 and 2.3\u00a0hours. The highest C<jats:sub>10<\/jats:sub> value, which may indicate rapid activity onset, and the highest C<jats:sub>max<\/jats:sub> were observed following administration of F<jats:sub>A<\/jats:sub> (40\u00a0mg\/kg): C<jats:sub>10<\/jats:sub>\u00a0=\u00a03.5\u00a0mg\/L and C<jats:sub>max<\/jats:sub>\u00a0=\u00a09.5\u00a0mg\/L. In the MEST test, (2S,3S)\u2010SPD (20 and 60\u00a0mg\/kg) significantly raised the tonic seizure threshold compared to vehicle at 4, 7, 10, and 20\u00a0minutes after dosing, with a 1.6\u2010fold increase at 20\u00a0minutes, which coincided with (2S,3S)\u2010SPD brain C<jats:sub>max<\/jats:sub>. Following intramuscular dosing of (2S,3S)\u2010SPD (12\u00a0mg\/kg) to pigs of F<jats:sub>A<\/jats:sub> and F<jats:sub>B<\/jats:sub>, a C<jats:sub>max<\/jats:sub> value of 0.9\u00a0mg\/L was obtained 0.42 and 0.75\u00a0hours after dosing, respectively. (2S,3S)\u2010SPD C<jats:sub>10<\/jats:sub> was 0.27\u00a0mg\/L (F<jats:sub>A<\/jats:sub>) and 0.49\u00a0mg\/L (F<jats:sub>B<\/jats:sub>). (2S,3S)\u2010SPD clearance, volume of distribution, and half\u2010life were 2\u00a0L\/h\/kg, 18\u201028\u00a0L\/kg, and 6.1\u20109.7\u00a0hours, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>(2S,3S)\u2010SPD demonstrated a good PK\u2010PD correlation in the rat MEST test, with a rapid onset. (2S,3S)\u2010SPD first PK study in pigs showed that doses &gt;12\u00a0mg\/kg are required to achieve in pigs the plasma concentrations associated with activity at the rat MEST test.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16411","type":"journal-article","created":{"date-parts":[[2020,1,20]],"date-time":"2020-01-20T10:55:10Z","timestamp":1579517710000},"page":"149-156","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacokinetic and pharmacodynamic analysis of (2S,3S)\u2010<i>sec<\/i>\u2010butylpropylacetamide (SPD) in rats and pigs\u2014A CNS\u2010active stereoisomer of SPD"],"prefix":"10.1111","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4018-7925","authenticated-orcid":false,"given":"David","family":"Bibi","sequence":"first","affiliation":[{"name":"Institute of Drug Research School of Pharmacy Faculty of Medicine The Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-4171","authenticated-orcid":false,"given":"Meir","family":"Bialer","sequence":"additional","affiliation":[{"name":"Institute of Drug Research School of Pharmacy Faculty of Medicine The Hebrew University of Jerusalem Jerusalem Israel"},{"name":"Affiliated with the David R. 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