{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:48:54Z","timestamp":1788241734645,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Deutetrabenazine (Austedo) is indicated in adults for chorea associated with Huntington disease and tardive dyskinesia. Escalating deutetrabenazine doses were administered to healthy volunteers who were cytochrome P450 2D6 extensive\/intermediate metabolizers (EMs) or poor metabolizers (PMs) to determine pharmacokinetic exposure of parent drug and active metabolites (\u03b1\u2010dihydrotetrabenazine [\u03b1\u2010HTBZ] and \u03b2\u2010dihydrotetrabenazine [\u03b2\u2010HTBZ]), and collect corresponding electrocardiograms (ECGs) for evaluation of the cardiodynamic effect using concentration\u2010QTc (C\u2010QTc) modeling. Participants (12 EMs, 24 PMs) received placebo or single doses of deutetrabenazine (24, 48, and 72\u00a0mg) to achieve plasma concentrations exceeding therapeutic range in both cohorts. Pharmacokinetic samples were obtained over 72 hours after dosing and were time matched with 12\u2010lead ECGs extracted from continuous ECG recordings. C\u2010QTc analysis, using linear mixed\u2010effects modeling and model selection procedure, characterized the relationship between plasma concentrations of deutetrabenazine, deuterated \u03b1\u2010HTBZ and \u03b2\u2010HTBZ, and the change from baseline in QT interval corrected using Fridericia's formula. Deutetrabenazine exhibited linear kinetics, and a C\u2010QTc model with deuterated \u03b1\u2010HTBZ and \u03b2\u2010HTBZ was selected to best describe the C\u2010QTc relationship in pooled EM and PM data. This model predicted a placebo\u2010corrected Fridericia corrected QT interval prolongation higher than 10 milliseconds can be excluded at concentrations associated with the maximum recommended doses in both populations. Adverse events increased with higher exposure as reflected by the higher event number in the PM cohort receiving 48 and 72\u00a0mg doses. No subject discontinued due to cardiac\u2010related adverse events and no clinically relevant ECG findings were reported. Thus, this study found that deutetrabenazine does not have a clinically relevant effect on QT prolongation at maximum recommended doses in either cytochrome P450 2D6 EMs or PMs.<\/jats:p>","DOI":"10.1002\/cpdd.1161","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T14:31:06Z","timestamp":1663079466000},"page":"94-106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Evaluation of Deutetrabenazine's Potential to Delay Cardiac Repolarization Using Concentration\u2010QTc Analysis"],"prefix":"10.1002","volume":"12","author":[{"given":"Frank","family":"Schneider","sequence":"first","affiliation":[{"name":"Teva Pharmaceutical Industries Ltd  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borje","family":"Darpo","sequence":"additional","affiliation":[{"name":"Clario  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pippa S.","family":"Loupe","sequence":"additional","affiliation":[{"name":"Teva Pharmaceuticals  West Chester Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqi","family":"Xue","sequence":"additional","affiliation":[{"name":"Clario  Pittsford New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Knebel","sequence":"additional","affiliation":[{"name":"Teva Pharmaceutical Industries Ltd  Netanya Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Teva Clinics Miramar  Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Forrest","family":"Gordon","sequence":"additional","affiliation":[{"name":"Teva Pharmaceuticals  West Chester Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rabinovich\u2010Guilatt","sequence":"additional","affiliation":[{"name":"Teva Pharmaceutical Industries Ltd  Netanya Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000198586.85250.13"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.8655"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003960"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(17)30236-5"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/14656566.2019.1674281"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/14737175.2018.1403899"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318263c443"},{"issue":"2","key":"e_1_2_8_9_1","first-page":"81","article-title":"The use of stable isotopes in pharmacological research","volume":"33","author":"Baillie TA","year":"1981","journal-title":"Pharmacol Rev."},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1139\/y99-005"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12754"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.882"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-021-03202-0"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.31.3.289"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.2165\/11208330-000000000-00000"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.4140\/TCP.n.2009.524"},{"issue":"16","key":"e_1_2_8_17_1","article-title":"A randomized double\u2010blind placebo\u2010 and positive\u2010controlled crossover study to evaluate the effects of single doses of SD\u2010809 (Deutetrabenazine) and tetrabenazine on the corrected QT interval","volume":"86","author":"Stamler D.","year":"2016","journal-title":"Neurology"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/anec.12227"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9558-5"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40246\u2010016\u20100073\u20103"},{"issue":"4","key":"e_1_2_8_21_1","first-page":"401","article-title":"Improving the precision of QT measurements","volume":"18","author":"Darpo B","year":"2011","journal-title":"Cardiol J."},{"key":"e_1_2_8_22_1","unstructured":"Ferber G.Issues with exposure\u2010response analysis: How we close the gap. Presentation on \u201cNew Advances in the Assessment of Drug\u2010Induced Arrhythmias and the Comprehensive In Vitro Proarrhythmia Assay (CiPA)\u201d Cardiac Safety Research Consortium (CSRC) HESI meeting. May 21\u201322 2018.[Abstract]."},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270010378408"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.779"},{"key":"e_1_2_8_25_1","article-title":"Population pharmacokinetic and exposure efficacy analyses of deutetrabenazine in patients with moderate to severe tardive dyskinesia","volume":"2","author":"Levi M","year":"2020","journal-title":"ACoP11"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002280050163"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1177\/009127000004000108"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.889"},{"issue":"3","key":"e_1_2_8_29_1","first-page":"61","article-title":"Long\u2010term safety and tolerability of valbenazine (NBI\u201098854) in subjects with tardive dyskinesia and a diagnosis of schizophrenia or mood disorder","volume":"47","author":"Josiassen RC","year":"2017","journal-title":"Psychopharmacol Bull."}],"container-title":["Clinical Pharmacology in Drug Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.1161","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpdd.1161","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.1161","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T22:23:44Z","timestamp":1692570224000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/cpdd.1161"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,13]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1]]}},"alternative-id":["10.1002\/cpdd.1161"],"URL":"https:\/\/doi.org\/10.1002\/cpdd.1161","archive":["Portico"],"relation":{},"ISSN":["2160-763X","2160-7648"],"issn-type":[{"value":"2160-763X","type":"print"},{"value":"2160-7648","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,13]]},"assertion":[{"value":"2022-06-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}