{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T14:18:38Z","timestamp":1781705918619,"version":"3.54.5"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,4,20]],"date-time":"2019-04-20T00:00:00Z","timestamp":1555718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Increased activity of T\u2010type Ca<jats:sup>2+<\/jats:sup> channels is linked to idiopathic generalized epilepsies, thus blocking these channels may be a new treatment option. <jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010709478 is an orally available triple T\u2010type Ca<jats:sup>2+<\/jats:sup> channel blocker. The aim of this first\u2010in\u2010man study was to investigate the pharmacokinetics, pharmacodynamics, tolerability, and safety of single doses of <jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010709478 in healthy subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This double\u2010blind, placebo\u2010controlled, randomized study included 65 healthy male subjects. Ascending single oral doses of 1\u2010400\u00a0mg <jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010709478 or placebo were administered to sequential groups of eight subjects (6 on active, 2 on placebo). Effect of food was tested in a crossover part at 60\u00a0mg. Blood and saliva sampling for pharmacokinetic evaluations and safety assessments was performed regularly. Effects on the central nervous system were assessed with a battery of pharmacodynamic tests.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The maximum plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) was reached within 3 to 4\u00a0hours (\u226460\u00a0mg) and within 20 to 28\u00a0hours (&gt;60\u00a0mg), and across all dose levels the terminal half\u2010life (95% confidence interval) ranged from 36 (29\u201045) to 43 (22\u201086) hours. Multiple peaks were observed and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> and <jats:styled-content style=\"fixed-case\">area under the plasma concentration\u2010time curve (AUC)<\/jats:styled-content><jats:sub>0\u2010\u221e<\/jats:sub> increased in a less than dose\u2010proportional manner. A 1.6\u2010fold increase in <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> and no change in <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2010\u221e<\/jats:sub> was observed in fed compared to fasted conditions. A significant correlation (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) between plasma and saliva concentrations was established using linear regression. All adverse events were transient and of mild or moderate intensity. No treatment\u2010related effects on vital signs, clinical laboratory, telemetry, or electrocardiography were detected. The results of pharmacodynamic tests did not show relevant mean changes compared to baseline or placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010709478 exhibits good tolerability and safety after single\u2010dose administration and its pharmacokinetic and pharmacodynamic properties warrant further investigations.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.14732","type":"journal-article","created":{"date-parts":[[2019,4,20]],"date-time":"2019-04-20T07:59:54Z","timestamp":1555747194000},"page":"968-978","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["First\u2010in\u2010man study of <scp>ACT<\/scp>\u2010709478, a novel selective triple T\u2010type calcium channel blocker"],"prefix":"10.1111","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0295-7730","authenticated-orcid":false,"given":"Muriel","family":"Richard","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology Idorsia Pharmaceuticals Ltd Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priska","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Idorsia Pharmaceuticals Ltd Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcdiger","family":"Kornberger","sequence":"additional","affiliation":[{"name":"Parexel International GmbH Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Dingemanse","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Idorsia Pharmaceuticals Ltd Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.57.4.5"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-06-01912.1999"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00018.2002"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-06-01895.1999"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1461-y"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1353-6"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00002.2006"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-009-0772-x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2019.01.008"},{"key":"e_1_2_8_11_1","first-page":"467","article-title":"Calcium channelopathies in inherited neurological disorders: relevance to drug screening for acquired channel disorders","volume":"13","author":"Lory P","year":"2010","journal-title":"IDrugs"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01236"},{"key":"e_1_2_8_13_1","first-page":"776","article-title":"Epilepsy management: newer agents, unmet needs, and future treatment strategies","volume":"39","author":"Ventola CL","year":"2014","journal-title":"P T"},{"key":"e_1_2_8_14_1","unstructured":"US Food and Drug Administration.Guidance for industry: food effect bioavailability and fed bioequivalence studies. 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