{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T06:00:11Z","timestamp":1773381611812,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>This analysis assessed the relationship between the plasma concentrations of loperamide and its <jats:italic>N<\/jats:italic>\u2010desmethyl loperamide meta\u2010 bolite (M1) and the potential QT interval prolongation at therapeutic and supratherapeutic doses. The exposure\u2013response analysis was performed using the data from healthy adults participating in a randomized, double\u2010blind, single\u2010dose, four\u2010way (placebo; loperamide 8\u2009mg [therapeutic]; loperamide 48\u2009mg [supratherapeutic]; moxifloxacin 400\u2009mg [positive control]) crossover study. The electrocardiographic measurements extracted from 12\u2010lead digital Holter recordings were time\u2010matched to pharmacokinetic sampling of loperamide\/M1. The primary response variable was placebo\u2010adjusted change from baseline in Fridericia\u2010corrected QT interval (\u0394\u0394QTcF); the exposure variable was loperamide and\/or M1 concentration. A total of 53 participants with 1408 time\u2010matched pharmacokinetic and \u0394\u0394QTcF measurements was analyzed. Hysteresis between both loperamide and M1 concentrations and \u0394\u0394QTcF was observed with supratherapeutic dose. The pre\u2010specified linear concentration\u2010\u0394\u0394QTcF relationship was driven by M1 concentrations in the effect compartment. The model\u2010predicted mean \u0394\u0394QTcF at the geometric mean of the maximum concentration in the effect compartment was \u22120.526\u2009msec (90% CI, \u22121.51 to 0.462) following 8\u2010mg dose (2.1\u2009ng\/mL) and 6.06\u2009msec (90% CI, 3.86\u20138.27) following 48\u2010mg dose (14.2 ng\/mL). The upper bound of two\u2010sided 90% CI was &lt;\u200910\u2009msec for both doses. The sensitivity analysis considering loperamide concentrations in the effect compartment instead of M1 as input for the concentration\u2010\u0394\u0394QTcF analysis confirmed these findings. The data showed that loperamide or M1 does not have an effect on cardiac repolarization that exceeds the threshold of regulatory concern in healthy participants at doses of 8 and 48\u2009mg.<\/jats:p>","DOI":"10.1111\/cts.70114","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T04:40:31Z","timestamp":1737952831000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evaluation of the Effect of Loperamide on the Cardiac Repolarization Interval Using Exposure\u2013Response Analysis"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2317-5028","authenticated-orcid":false,"given":"Bel\u00e9n","family":"Valenzuela","sequence":"first","affiliation":[{"name":"Janssen\u2010Cilag Spain Part of Janssen Pharmaceutical Companies of Johnson and Johnson  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0706-8783","authenticated-orcid":false,"given":"Per Olsson","family":"Gisleskog","sequence":"additional","affiliation":[{"name":"POG Pharmacometrics  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8710-5003","authenticated-orcid":false,"given":"Iolanda","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Janssen Clinical Pharmacology and Pharmacometrics  Raritan New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0601-9373","authenticated-orcid":false,"given":"Erwin","family":"Coenen","sequence":"additional","affiliation":[{"name":"Janssen Clinical Pharmacology and Pharmacometrics  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay","family":"Ariyawansa","sequence":"additional","affiliation":[{"name":"Janssen Statistical and Decision Sciences  Raritan New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saberi Rana","family":"Ali","sequence":"additional","affiliation":[{"name":"Janssen Established Products  Titusville New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7406-3095","authenticated-orcid":false,"given":"Samiha","family":"Takhtoukh","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica Clinical Pharmacology Unit  Merksem Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-745X","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"P\u00e9rez\u2010Ruixo","sequence":"additional","affiliation":[{"name":"Janssen\u2010Cilag Spain Part of Janssen Pharmaceutical Companies of Johnson and Johnson  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5908-5200","authenticated-orcid":false,"given":"Oliver","family":"Ackaert","sequence":"additional","affiliation":[{"name":"Janssen Clinical Pharmacology and Pharmacometrics  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,1,27]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"Johnson & Johnson Consumer Inc \u201cIMODIUM Label \u201d(2016) https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2016\/017694s052lbl.pdf."},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpainsymman.2011.06.001"},{"issue":"12","key":"e_1_2_9_4_1","article-title":"Loperamide\u2010Induced Cardiac Events: Case Reports and Review","volume":"13","author":"Modi V.","year":"2021","journal-title":"Cureus"},{"issue":"3","key":"e_1_2_9_5_1","first-page":"S11","article-title":"Loperamide: A Pharmacological Review","volume":"7","author":"Baker D. 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