{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T02:08:17Z","timestamp":1783822097903,"version":"3.55.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"},{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"funder":[{"name":"Innovative Medicines R&D Global Clinical Development Teva Pharmaceuticals Netanya Israel"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Drug Investig"],"published-print":{"date-parts":[[2026,8]]},"DOI":"10.1007\/s40261-026-01566-8","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T18:34:22Z","timestamp":1781894062000},"page":"911-923","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of Dose Proportionality and the Effect of Food on a Once-Daily Extended-Release Tablet Formulation of Deutetrabenazine in Healthy Participants"],"prefix":"10.1007","volume":"46","author":[{"given":"Eva-Maria","family":"Sunzel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Ghibellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gutierrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra","family":"Ruffo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailendra","family":"Chavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagnath G.","family":"Birajdar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2161-5050","authenticated-orcid":false,"given":"Pippa","family":"Loupe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Forrest","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rabinovich-Guilatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"issue":"8","key":"1566_CR1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/S2215-0366(17)30236-5","volume":"4","author":"KE Anderson","year":"2017","unstructured":"Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind randomized placebo-controlled phase 3 trial. Lancet Psychiat. 2017;4(8):595\u2013604.","journal-title":"Lancet Psychiat"},{"issue":"1","key":"1566_CR2","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1001\/jama.2016.8655","volume":"316","author":"Huntington Study Group","year":"2016","unstructured":"Huntington Study Group. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. JAMA. 2016;316(1):40\u201350.","journal-title":"JAMA"},{"issue":"21","key":"1566_CR3","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1212\/WNL.0000000000003960","volume":"88","author":"HH Fernandez","year":"2017","unstructured":"Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia. Neurology. 2017;88(21):2003\u201310.","journal-title":"Neurology"},{"key":"1566_CR4","first-page":"545","volume":"3","author":"D Paleacu","year":"2007","unstructured":"Paleacu D. Tetrabenazine in the treatment of Huntington\u2019s disease. Neuropsychiatr Dis Treat. 2007;3:545\u201351.","journal-title":"Neuropsychiatr Dis Treat"},{"key":"1566_CR5","unstructured":"Xenazine prescribing information. Treatment for chorea associated with Huntington\u2019s disease. Xenazine (tetrabenazine) tablets. Bausch Health Companies Inc. https:\/\/www.xenazineusa.com\/. Accessed 15 Dec 2025."},{"key":"1566_CR6","unstructured":"Barak Boner N, Magid L, Griffin T, Schmukler E, Fishbein I. Potency and specificity of deutetrabenazine deuterated metabolites for VMAT2 as confirmed by binding affinity and functional activity studies. In: Poster presented at: NEI Spring Institute; 8\u201310, May 2025; Philadelphia (PA)."},{"key":"1566_CR7","first-page":"690","volume":"33","author":"T Yero","year":"2008","unstructured":"Yero T, Rey JA. Tetrabenazine (Xenazine), an FDA-approved treatment option for Huntington\u2019s disease-related chorea. P T. 2008;33:690\u20134.","journal-title":"P T"},{"key":"1566_CR8","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/S0031-6997(25)06851-6","volume":"3","author":"TA Baillie","year":"1981","unstructured":"Baillie TA. The use of stable isotopes in pharmacological research. Pharmacol Rev. 1981;3:81\u2013132.","journal-title":"Pharmacol Rev"},{"key":"1566_CR9","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1139\/y99-005","volume":"77","author":"DJ Kushner","year":"1999","unstructured":"Kushner DJ, Baker A, Dunstall TG. Pharmacological uses and perspectives of heavy water and deuterated compounds. Can J Physiol Pharmacol. 1999;77:79\u201388.","journal-title":"Can J Physiol Pharmacol"},{"issue":"4","key":"1566_CR10","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1111\/cts.12754","volume":"13","author":"F Schneider","year":"2020","unstructured":"Schneider F, Bradbury M, Baillie TA, et al. Pharmacokinetic and metabolic profile of deutetrabenazine (TEV-50717) compared with tetrabenazine in healthy volunteers. Clin Transl Sci. 2020;13(4):707\u201317.","journal-title":"Clin Transl Sci"},{"key":"1566_CR11","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1038\/s41573-023-00703-8","volume":"22","author":"CRM Di Martino","year":"2023","unstructured":"Di Martino CRM, Maxwell BD, Pirali T. Deuterium in drug discovery: progress, opportunities and challenges. Nat Rev Drug Discov. 2023;22:562\u201384.","journal-title":"Nat Rev Drug Discov"},{"issue":"6","key":"1566_CR12","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1002\/cpdd.882","volume":"10","author":"F Schneider","year":"2021","unstructured":"Schneider F, Stamler D, Bradbury M, et al. Pharmacokinetics of deutetrabenazine and tetrabenazine: dose proportionality and food effect. Clin Pharmacol Drug Dev. 2021;10(6):647\u201359.","journal-title":"Clin Pharmacol Drug Dev."},{"key":"1566_CR13","unstructured":"Austedo XR and Austedo Prescribing Information. Teva Neuroscience, Inc. 2025. https:\/\/www.austedo.com\/globalassets\/austedo\/prescribing-information.pdf. Accessed 5 Dec 2025."},{"issue":"3","key":"1566_CR14","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1002\/cpdd.1355","volume":"13","author":"EM Sunzel","year":"2024","unstructured":"Sunzel EM, Rabinovich-Guilatt L, Iyengaar M, et al. A bioequivalence comparison at steady state between the newly developed once-daily extended-release tablet formulation and the approved twice-daily table formulation of deutetrabenazine. Clin Pharmacol Drug Dev. 2024;13(3):224\u201332. https:\/\/doi.org\/10.1002\/cpdd.1355.","journal-title":"Clin Pharmacol Drug Dev."},{"key":"1566_CR15","unstructured":"U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Bioavailability studies submitted in NDAs or INDs: general considerations. Guidance for industry. Draft guidance issued February 2019. Final guidance April 2022. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/bioavailability-studies-submitted-ndas-or-inds-general-considerations. Accessed 12 Jan 2026."},{"key":"1566_CR16","doi-asserted-by":"publisher","DOI":"10.3390\/ph15111430","volume":"15","author":"Y Almoshari","year":"2022","unstructured":"Almoshari Y. Osmotic pump drug delivery systems: a comprehensive review. Pharmaceuticals. 2022;15:1430.","journal-title":"Pharmaceuticals"},{"key":"1566_CR17","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.ejpb.2009.07.002","volume":"73","author":"V Malaterre","year":"2009","unstructured":"Malaterre V, Ogorka J, Loggia N, Gurny R. Oral osmotically driven systems: 30 years of development and clinical use. Eur J Pharm Biopharm. 2009;73:311\u201323.","journal-title":"Eur J Pharm Biopharm"},{"key":"1566_CR18","unstructured":"U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for industry: food-effect bioavailability and fed bioequivalence studies. December 2002 BP. https:\/\/www.fda.gov\/files\/drugs\/published\/Food-Effect-Bioavailability-and-Fed-Bioequivalence-Studies.pdf. Accessed 5 Dec 2025."},{"key":"1566_CR19","unstructured":"U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Assessing the effects of food on drugs in INDs and NDAs: clinical pharmacology considerations. Guidance for Industry. June 2022. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/assessing-effects-food-drugs-inds-and-ndas-clinical-pharmacology-considerations. Accessed 12 Jan 2026."},{"key":"1566_CR20","unstructured":"U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Bioanalytical method validation guidance for industry. May 2018. https:\/\/www.fda.gov\/files\/drugs\/published\/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf. Accessed 9 Jan 2026."},{"key":"1566_CR21","unstructured":"European Medicines Agency Science Medicine Health. Committee for Medicinal Products for Human Use. Guideline on bioanalytical method validation. 2015. https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-bioanalytical-method-validation_en.pdf. Accessed 9 Jan 2026."},{"issue":"10","key":"1566_CR22","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1023\/A:1026451721686","volume":"17","author":"BP Smith","year":"2000","unstructured":"Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, et al. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 2000;17(10):1278\u201383.","journal-title":"Pharm Res"},{"key":"1566_CR23","unstructured":"Jain R, Konings M, Thompson S, Yang A, Kotak S, Gandhi P. Real-world evidence of patient experience with once-daily deutetrabenazine extended-release tablets for the treatment of tardive dyskinesia in the United States. In: Poster presented at: annual psych congress elevate; 28\u201331 May, 2025; Las Vegas (NV)."},{"key":"1566_CR24","unstructured":"Bulica B, Konings M, Thompson S, Yang A, Kotak S, Gandhi P. Patient experience and satisfaction with once-daily deutetrabenazine extended-release tablets for treatment of Huntington disease-related chorea [abstract]. Mov Disord. 2025;40(Suppl. 1). https:\/\/www.mdsabstracts.org\/abstract\/patient-experience-and-satisfaction-with-once-daily-deutetrabenazine-extended-release-tablets-for-treatment-of-huntington-disease-related-chorea\/. Accessed 26 May 2026."},{"key":"1566_CR25","unstructured":"Singh R, Sunzel EM, Kang D, Gordon MF, Rabinovich-Guilatt L, Ghibellini G. Exposure-response analysis to compare changes in the clinical endpoints for tardive dyskinesia and chorea in Huntington's disease following once-daily and twice-daily tablet formulations of deutetrabenazine. Poster presented at: Schizophrenia International Research Society annual meeting; 11\u201315 May, 2023; Toronto (ON). https:\/\/pmg.joynadmin.org\/documents\/1007\/6459484d5f7cef53da14f9e3.pdf. S37 pages 462-463. Accessed 29 May 2026."},{"key":"1566_CR26","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1002\/pst.326","volume":"8","author":"J Hummel","year":"2009","unstructured":"Hummel J, McKendrick S, Brindley C, French R. Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion. Pharm Stat. 2009;8:38\u201349.","journal-title":"Pharm Stat"},{"key":"1566_CR27","doi-asserted-by":"publisher","first-page":"526","DOI":"10.2174\/138920010791636185","volume":"11","author":"Y Sheng","year":"2010","unstructured":"Sheng Y, He Y, Huang X, Yang J, Wang K, Zheng Q. Systematic evaluation of dose proportionality studies in clinical pharmacokinetics. Curr Drug Metabol. 2010;11:526\u201337.","journal-title":"Curr Drug Metabol"}],"container-title":["Clinical Drug Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40261-026-01566-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40261-026-01566-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40261-026-01566-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T02:02:29Z","timestamp":1783821749000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40261-026-01566-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,19]]},"references-count":27,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["1566"],"URL":"https:\/\/doi.org\/10.1007\/s40261-026-01566-8","relation":{},"ISSN":["1173-2563","1179-1918"],"issn-type":[{"value":"1173-2563","type":"print"},{"value":"1179-1918","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,19]]},"assertion":[{"value":"4 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Giulia Ghibellini, Debra Ruffo, Nagnath G. Birajdar, Frank Schneider, Pippa Loupe, and Laura Rabinovich-Guilatt are employees of Teva Pharmaceuticals and are eligible for stock options in Teva. Shailendra Chavan was a Teva employee at the time of his death. Eva-Maria Sunzel, Maria Gutierrez, and Mark Forrest Gordon are former employees of Teva Pharmaceuticals and were eligible for stock options in Teva at the time the studies were conducted.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest\/competing interests"}},{"value":"The two open-label studies in heathy participants (Study TV50717-PK-10175 and Study TV50717-BE-10165) were conducted in adherence to the Declaration of Helsinki and in full accordance with the International Council for Harmonization Harmonized Guideline for Good Clinical Practice E6(R2) and any applicable national and local laws and regulations. An institutional research ethics committee reviewed and approved the studies (Advarra Institutional Review Board, Columbia, MD, USA) for Center #14426 on 22 September, 2019. The studies were conducted from June to July 2021 at Teva Internal Clinics in Miramar, FL, USA with Maria Gutierrez, MD as the principal investigator.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all participants included in the studies.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The datasets used and\/or analyzed for the described studies are available upon reasonable request. Qualified researchers may request access to patient-level data and related study documents, including the study protocols and the statistical analysis plans. Patient-level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please visit\n                      \n                      to make your request.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of data and material"}},{"value":"Not applicable.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}},{"value":"Conceptualization: E-MS, GG, FS, LR-G. Methodology: E-MS, MG, DR, SC, NGB. Investigation: E-MS, MG, DR, SC, NGB. Interpretation: E-MS, GG, MG, DR, SC, NGB, PL, FS, MFG, LR-G. Writing original draft: E-MS, PL. Writing (review and editing): GG, MG, DR, SC, NGB, FS, MFG, LR-G. All authors have read and agreed to the final version of the article.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 contributions"}}]}}