{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T04:22:33Z","timestamp":1771474953447,"version":"3.50.1"},"reference-count":22,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2016,8,4]],"date-time":"2016-08-04T00:00:00Z","timestamp":1470268800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Eisai Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2017,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration\u2013response (CR) modeling applied to data from 2 multiple ascending\u2010dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to \u201cbridge\u201d pharmacokinetic and safety data between Japanese and non\u2010Japanese subjects (J\u2010MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high\u2010precision measurement technique and evaluated using a linear mixed\u2010effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was \u20130.00002 milliseconds per ng\/mL (90%CI, \u20130.01019 to 0.01014 milliseconds). The highest observed C<jats:sub>max<\/jats:sub> was 400 ng\/mL, representing a margin 8\u2010fold above exposures expected for the highest planned clinical dose. The model\u2010predicted QTc effect at 400 ng\/mL was 1.1 milliseconds (90%CI, \u20133.49 to 5.78 milliseconds). In neither the J\u2010MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early\u2010phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect &gt;10\u00a0milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies.<\/jats:p>","DOI":"10.1002\/jcph.785","type":"journal-article","created":{"date-parts":[[2016,6,24]],"date-time":"2016-06-24T09:16:50Z","timestamp":1466759810000},"page":"96-104","source":"Crossref","is-referenced-by-count":32,"title":["Concentration\u2013Response Modeling of ECG Data From Early\u2010Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk \u2014 Experience From the Development Program of Lemborexant"],"prefix":"10.1002","volume":"57","author":[{"given":"Patricia J.","family":"Murphy","sequence":"first","affiliation":[{"name":"Eisai Inc  Woodcliff Lake NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanae","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Eisai Co., Ltd  Bunkyo\u2010ku Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenya","family":"Nakai","sequence":"additional","affiliation":[{"name":"Eisai Co., Ltd  Bunkyo\u2010ku Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Yoshinaga","sequence":"additional","affiliation":[{"name":"Eisai Co., Ltd  Bunkyo\u2010ku Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Hall","sequence":"additional","affiliation":[{"name":"Eisai Inc  Woodcliff Lake NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meijian","family":"Zhou","sequence":"additional","affiliation":[{"name":"iCardiac Technologies  Rochester NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jagadeesh","family":"Aluri","sequence":"additional","affiliation":[{"name":"Eisai Inc  Woodcliff Lake NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhaskar","family":"Rege","sequence":"additional","affiliation":[{"name":"Eisai Inc  Woodcliff Lake NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret","family":"Moline","sequence":"additional","affiliation":[{"name":"Eisai Inc  Woodcliff Lake NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jim","family":"Ferry","sequence":"additional","affiliation":[{"name":"Eisai Inc  Woodcliff Lake NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borje","family":"Darpo","sequence":"additional","affiliation":[{"name":"iCardiac Technologies  Rochester NY USA"},{"name":"Karolinska Institute  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,8,4]]},"reference":[{"key":"e_1_2_7_2_1","unstructured":"ICH Harmonized Tripartite Guideline E14.The Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drugs.2005.http:\/\/www.ich.org\/fileadmin\/Public_Web_Site\/ICH_Products\/Guidelines\/Efficacy\/E14\/E14_Guideline.pdf."},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100294"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543400802020938"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270007311921"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12068"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270008323261"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03261967"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/anec.12128"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.60"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/anec.12127"},{"key":"e_1_2_7_12_1","unstructured":"GarnettCE.Value of evaluation concentration: QTc relationship in regulatory decision making. 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