{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:10:53Z","timestamp":1785928253954,"version":"3.56.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/100005646","name":"Actelion Pharmaceuticals","doi-asserted-by":"publisher","award":["AC-083-102"],"award-info":[{"award-number":["AC-083-102"]}],"id":[{"id":"10.13039\/100005646","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016198","name":"Idorsia Pharmaceuticals","doi-asserted-by":"crossref","award":["AC-083-102"],"award-info":[{"award-number":["AC-083-102"]}],"id":[{"id":"10.13039\/501100016198","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["CNS Drugs"],"published-print":{"date-parts":[[2020,3]]},"DOI":"10.1007\/s40263-019-00697-1","type":"journal-article","created":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T06:04:39Z","timestamp":1580191479000},"page":"311-323","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Multiple-Ascending Dose Study in Healthy Subjects to Assess the Pharmacokinetics, Tolerability, and CYP3A4 Interaction Potential of the T-Type Calcium Channel Blocker ACT-709478, A Potential New Antiepileptic Drug"],"prefix":"10.1007","volume":"34","clinical-trial-number":[{"clinical-trial-number":"nct03165097","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0295-7730","authenticated-orcid":false,"given":"Muriel","family":"Richard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2415-3012","authenticated-orcid":false,"given":"Priska","family":"Kaufmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9308-5853","authenticated-orcid":false,"given":"Marion","family":"Ort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcdiger","family":"Kornberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-5817","authenticated-orcid":false,"given":"Jasper","family":"Dingemanse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,28]]},"reference":[{"issue":"1","key":"697_CR1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.neurol.2015.11.003","volume":"172","author":"C Behr","year":"2016","unstructured":"Behr C, Goltzene MA, Kosmalski G, Hirsch E, Ryvlin P. Epidemiology of epilepsy. Rev Neurol (Paris). 2016;172(1):27\u201336.","journal-title":"Rev Neurol (Paris)."},{"issue":"Suppl. 9","key":"697_CR2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1111\/j.1528-1167.2005.00309.x","volume":"46","author":"P Jallon","year":"2005","unstructured":"Jallon P, Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia. 2005;46(Suppl. 9):10\u20134.","journal-title":"Epilepsia"},{"issue":"4","key":"697_CR3","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.yebeh.2010.02.005","volume":"17","author":"JP Szaflarski","year":"2010","unstructured":"Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Seizure control in patients with idiopathic generalized epilepsies: eEG determinants of medication response. Epilepsy Behav. 2010;17(4):525\u201330.","journal-title":"Epilepsy Behav"},{"issue":"10","key":"697_CR4","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1056\/NEJMra1004418","volume":"365","author":"P Kwan","year":"2011","unstructured":"Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365(10):919\u201326.","journal-title":"N Engl J Med"},{"issue":"11","key":"697_CR5","first-page":"776","volume":"39","author":"CL Ventola","year":"2014","unstructured":"Ventola CL. Epilepsy management: newer agents, unmet needs, and future treatment strategies. PT. 2014;39(11):776\u201392.","journal-title":"PT"},{"issue":"Suppl. 4","key":"697_CR6","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/epi.12294","volume":"54","author":"JA French","year":"2013","unstructured":"French JA, White HS, Klitgaard H, Holmes GL, Privitera MD, Cole AJ, et al. Development of new treatment approaches for epilepsy: unmet needs and opportunities. Epilepsia. 2013;54(Suppl. 4):3\u201312.","journal-title":"Epilepsia"},{"issue":"6","key":"697_CR7","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1523\/JNEUROSCI.19-06-01912.1999","volume":"19","author":"JH Lee","year":"1999","unstructured":"Lee JH, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klockner U, et al. Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family. J Neurosci. 1999;19(6):1912\u201321.","journal-title":"J Neurosci"},{"issue":"1","key":"697_CR8","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1152\/physrev.00018.2002","volume":"83","author":"E Perez-Reyes","year":"2003","unstructured":"Perez-Reyes E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev. 2003;83(1):117\u201361.","journal-title":"Physiol Rev"},{"issue":"6","key":"697_CR9","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1523\/JNEUROSCI.19-06-01895.1999","volume":"19","author":"EM Talley","year":"1999","unstructured":"Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA. Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci. 1999;19(6):1895\u2013911.","journal-title":"J Neurosci"},{"key":"697_CR10","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.biocel.2019.01.008","volume":"108","author":"N Weiss","year":"2019","unstructured":"Weiss N, Zamponi GW. T-type calcium channels: from molecule to therapeutic opportunities. Int J Biochem Cell Biol. 2019;108:34\u20139.","journal-title":"Int J Biochem Cell Biol"},{"issue":"3","key":"697_CR11","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1152\/physrev.00002.2006","volume":"86","author":"H Khosravani","year":"2006","unstructured":"Khosravani H, Zamponi GW. Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol Rev. 2006;86(3):941\u201366.","journal-title":"Physiol Rev"},{"issue":"2","key":"697_CR12","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1007\/s00424-009-0772-x","volume":"460","author":"GW Zamponi","year":"2010","unstructured":"Zamponi GW, Lory P, Perez-Reyes E. Role of voltage-gated calcium channels in epilepsy. Pflug Arch. 2010;460(2):395\u2013403.","journal-title":"Pflug Arch"},{"issue":"4","key":"697_CR13","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1007\/s00424-014-1461-y","volume":"466","author":"E Cheong","year":"2014","unstructured":"Cheong E, Shin HS. T-type Ca2\u2009+\u2009channels in absence epilepsy. Pflug Arch. 2014;466(4):719\u201334.","journal-title":"Pflug Arch"},{"issue":"23","key":"697_CR14","doi-asserted-by":"publisher","first-page":"9769","DOI":"10.1021\/acs.jmedchem.7b01236","volume":"60","author":"O Bezencon","year":"2017","unstructured":"Bezencon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, et al. Discovery of a potent, selective T-type calcium channel blocker as a drug candidate for the treatment of generalized epilepsies. J Med Chem. 2017;60(23):9769\u201389.","journal-title":"J Med Chem"},{"issue":"5","key":"697_CR15","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1111\/epi.14732","volume":"60","author":"M Richard","year":"2019","unstructured":"Richard M, Kaufmann P, Kornberger R, Dingemanse J. First-in-man study of ACT-709478, a novel selective triple T-type calcium channel blocker. Epilepsia. 2019;60(5):968\u201378.","journal-title":"Epilepsia"},{"key":"697_CR16","unstructured":"U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Draft guidance for industry: clinical drug interaction studies: study design, data analysis, and clinical implications. October 2017. Available from: https:\/\/www.fda.gov\/media\/82734\/download. Accessed 3 Jan 2020."},{"issue":"5","key":"697_CR17","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1093\/bja\/73.5.658","volume":"73","author":"C Wandel","year":"1994","unstructured":"Wandel C, Bocker R, Bohrer H, Browne A, Rugheimer E, Martin E. Midazolam is metabolized by at least three different cytochrome P450 enzymes. Br J Anaesth. 1994;73(5):658\u201361.","journal-title":"Br J Anaesth"},{"issue":"9","key":"697_CR18","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1007\/s00228-017-2282-7","volume":"73","author":"PE Juif","year":"2017","unstructured":"Juif PE, Boehler M, Donazzolo Y, Bruderer S, Dingemanse J. A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects. Eur J Clin Pharmacol. 2017;73(9):1121\u20138.","journal-title":"Eur J Clin Pharmacol"},{"issue":"11","key":"697_CR19","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1212\/WNL.25.11.1065","volume":"25","author":"RW Baloh","year":"1975","unstructured":"Baloh RW, Sills AW, Kumley WE, Honrubia V. Quantitative measurement of saccade amplitude, duration, and velocity. Neurology. 1975;25(11):1065\u201370.","journal-title":"Neurology."},{"issue":"2","key":"697_CR20","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1038\/clpt.1991.122","volume":"50","author":"AL van Steveninck","year":"1991","unstructured":"van Steveninck AL, Schoemaker HC, Pieters MS, Kroon R, Breimer DD, Cohen AF. A comparison of the sensitivities of adaptive tracking, eye movement analysis and visual analog lines to the effects of incremental doses of temazepam in healthy volunteers. Clin Pharmacol Ther. 1991;50(2):172\u201380.","journal-title":"Clin Pharmacol Ther"},{"issue":"2","key":"697_CR21","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1111\/j.1365-2125.1993.tb04205.x","volume":"36","author":"AL van Steveninck","year":"1993","unstructured":"van Steveninck AL, Mandema JW, Tuk B, van Dijk JG, Schoemaker HC, Danhof M, et al. A comparison of the concentration-effect relationships of midazolam for EEG-derived parameters and saccadic peak velocity. Br J Clin Pharmacol. 1993;36(2):109\u201315.","journal-title":"Br J Clin Pharmacol"},{"issue":"5","key":"697_CR22","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1038\/clpt.2010.19","volume":"87","author":"P Hoever","year":"2010","unstructured":"Hoever P, de Haas S, Winkler J, Schoemaker RC, Chiossi E, van Gerven J, et al. Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant. Clin Pharmacol Ther. 2010;87(5):593\u2013600.","journal-title":"Clin Pharmacol Ther"},{"issue":"2","key":"697_CR23","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1111\/j.1365-2125.2001.01308.x","volume":"51","author":"SJ de Visser","year":"2001","unstructured":"de Visser SJ, van der Post J, Pieters MS, Cohen AF, van Gerven JM. Biomarkers for the effects of antipsychotic drugs in healthy volunteers. Br J Clin Pharmacol. 2001;51(2):119\u201332.","journal-title":"Br J Clin Pharmacol"},{"issue":"1","key":"697_CR24","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1097\/00000542-199801000-00015","volume":"88","author":"TA Bowdle","year":"1998","unstructured":"Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP. Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology. 1998;88(1):82\u20138.","journal-title":"Anesthesiology"},{"issue":"8","key":"697_CR25","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1177\/0269881112448946","volume":"26","author":"P Hoever","year":"2012","unstructured":"Hoever P, de Haas SL, Dorffner G, Chiossi E, van Gerven JM, Dingemanse J. Orexin receptor antagonism: an ascending multiple-dose study with almorexant. J Psychopharmacol. 2012;26(8):1071\u201380.","journal-title":"J Psychopharmacol"},{"issue":"6","key":"697_CR26","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1111\/j.1365-2125.2011.03936.x","volume":"71","author":"M Liem-Moolenaar","year":"2011","unstructured":"Liem-Moolenaar M, de Boer P, Timmers M, Schoemaker RC, van Hasselt JG, Schmidt S, et al. Pharmacokinetic-pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects. Br J Clin Pharmacol. 2011;71(6):886\u201398.","journal-title":"Br J Clin Pharmacol"},{"issue":"7","key":"697_CR27","doi-asserted-by":"publisher","first-page":"1574","DOI":"10.1016\/j.clinph.2006.03.011","volume":"117","author":"K Kaida","year":"2006","unstructured":"Kaida K, Takahashi M, Akerstedt T, Nakata A, Otsuka Y, Haratani T, et al. Validation of the Karolinska sleepiness scale against performance and EEG variables. Clin Neurophysiol. 2006;117(7):1574\u201381.","journal-title":"Clin Neurophysiol"},{"issue":"3","key":"697_CR28","first-page":"1039","volume":"29","author":"K Gough","year":"1995","unstructured":"Gough K, Hutchison M, Keene O, Byrom B, Ellis S, Lacey I, et al. Assessment of dose proportionality: report from the statisticians in the pharmaceutical industry\/Pharmacokinetics UK Joint Working Party. Ther Innov Regul Sci. 1995;29(3):1039\u201348.","journal-title":"Ther Innov Regul Sci"},{"issue":"2","key":"697_CR29","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s00228-018-2559-5","volume":"75","author":"ML Boof","year":"2019","unstructured":"Boof ML, Alatrach A, Ufer M, Dingemanse J. Interaction potential of the dual orexin receptor antagonist ACT-541468 with CYP3A4 and food: results from two interaction studies. Eur J Clin Pharmacol. 2019;75(2):195\u2013205.","journal-title":"Eur J Clin Pharmacol"},{"issue":"6","key":"697_CR30","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1111\/j.1472-8206.2012.01060.x","volume":"27","author":"J Dingemanse","year":"2013","unstructured":"Dingemanse J, Nicolas L, Binkert C. Clinical pharmacology of single- and multiple-ascending doses of ACT-178882, a new direct renin inhibitor, and its pharmacokinetic interaction with food and midazolam. Fundam Clin Pharmacol. 2013;27(6):698\u2013710.","journal-title":"Fundam Clin Pharmacol"},{"issue":"3","key":"697_CR31","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1007\/s00228-012-1403-6","volume":"69","author":"M Hoch","year":"2013","unstructured":"Hoch M, Hoever P, Alessi F, Theodor R, Dingemanse J. Pharmacokinetic interactions of almorexant with midazolam and simvastatin, two CYP3A4 model substrates, in healthy male subjects. Eur J Clin Pharmacol. 2013;69(3):523\u201332.","journal-title":"Eur J Clin Pharmacol"},{"issue":"11","key":"697_CR32","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1007\/s00228-012-1287-5","volume":"68","author":"J Davis","year":"2012","unstructured":"Davis J, Langdon G, Layton G, Chong CL, Ndongo MN, Vourvahis M. The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects. Eur J Clin Pharmacol. 2012;68(11):1567\u201372.","journal-title":"Eur J Clin Pharmacol"},{"issue":"8","key":"697_CR33","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1007\/s00228-010-0814-5","volume":"66","author":"JH Tu","year":"2010","unstructured":"Tu JH, He YJ, Chen Y, Fan L, Zhang W, Tan ZR, et al. Effect of glycyrrhizin on the activity of CYP3A enzyme in humans. Eur J Clin Pharmacol. 2010;66(8):805\u201310.","journal-title":"Eur J Clin Pharmacol"},{"issue":"3","key":"697_CR34","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/S0896-6273(00)81057-0","volume":"25","author":"EA Ertel","year":"2000","unstructured":"Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E, et al. Nomenclature of voltage-gated calcium channels. Neuron. 2000;25(3):533\u20135.","journal-title":"Neuron"},{"issue":"8","key":"697_CR35","doi-asserted-by":"publisher","first-page":"a003947","DOI":"10.1101\/cshperspect.a003947","volume":"3","author":"WA Catterall","year":"2011","unstructured":"Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol. 2011;3(8):a003947.","journal-title":"Cold Spring Harb Perspect Biol"}],"container-title":["CNS Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40263-019-00697-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40263-019-00697-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40263-019-00697-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T17:54:13Z","timestamp":1628618053000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40263-019-00697-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,28]]},"references-count":35,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,3]]}},"alternative-id":["697"],"URL":"https:\/\/doi.org\/10.1007\/s40263-019-00697-1","relation":{},"ISSN":["1172-7047","1179-1934"],"issn-type":[{"value":"1172-7047","type":"print"},{"value":"1179-1934","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,28]]},"assertion":[{"value":"28 January 2020","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"This work was supported by Actelion Pharmaceuticals Ltd, the predecessor of Idorsia Pharmaceuticals Ltd, and Idorsia Pharmaceuticals Ltd.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"At the time of study conduct, Muriel Richard, Priska Kaufmann, and Jasper Dingemanse were employees at Actelion Pharmaceuticals Ltd (predecessor of Idorsia Pharmaceuticals Ltd) and Idorsia Pharmaceuticals Ltd. Marion Ort was an employee at Idorsia Pharmaceuticals Ltd. R\u00fcdiger Kornberger was an investigator of this study that was funded by Actelion Pharmaceuticals Ltd and Idorsia Pharmaceuticals Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee (ethics committee of Berlin) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"All subjects gave written informed consent prior to any study-mandated procedure.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed Consent"}}]}}