{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T11:23:40Z","timestamp":1782386620984,"version":"3.54.5"},"reference-count":33,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":19,"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":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Telemetry\u2010based methods are recommended as best practice for monitoring changes in cardiovascular (CV) function in conscious nonrodent species during the development of new chemical entities. Such methods allow for unrestrained data collection in animals over extended time periods with high sensitivity to detect small effects. The CV profile of new drugs is also assessed in repeat\u2010dose toxicology studies, routinely utilizing non\u2010invasive blood pressure, heart rate, and ECG measurement methods that require physical or chemical restraint. These methods are limited to a short \u201csnapshot\u201d data collection period and incur physiological stress and behavioral excitement from handling\/restraint during data collection. The resultant sympathetic activation impacts heart rate, blood pressure, and ECG intervals, causing increased variability and reduced sensitivity. Nonclinical best practices have been defined for standalone CV telemetry studies to support an integrated QTc risk assessment (ICH E14\/S7B Q&amp;A 5.1 &amp; 6.1) using non\u2010restraint telemetry methods; however, the pharmacological and statistical sensitivity of restraint\u2010based methods used in repeat\u2010dose toxicology studies is a gap. This paper retrospectively analyzed two case studies (AMG 319 and AMG 337) in which proprietary small molecules were evaluated by both non\u2010restraint\u2010based telemetry and restraint\u2010based methods. AMG 319 and AMG 337 caused QTc interval prolongation and hypotension, respectively, in telemetry studies, which were also observed clinically with these compounds. However, in toxicology studies in which restraint\u2010based ECG and blood pressure methods were used, CV effects were missed, blunted, or directionally wrong. These case studies highlight the need for the utilization of unrestrained telemetry methods over restraint\u2010based methods.<\/jats:p>","DOI":"10.1111\/cts.70249","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T02:04:45Z","timestamp":1747793085000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Restraint\u2010Based <scp>ECG<\/scp> and Arterial Pressure Assessment Do Not Reliably Detect Drug Induced <scp>QTc<\/scp> Prolongation and Hypotension: Evidence From Case Studies"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1964-8045","authenticated-orcid":false,"given":"Kim A.","family":"Henderson","sequence":"first","affiliation":[{"name":"Amgen Research, Translational Safety Research Amgen, Inc.  Thousand Oaks California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9453-9022","authenticated-orcid":false,"given":"Nicholas","family":"Ether","sequence":"additional","affiliation":[{"name":"Amgen Research, Translational Safety Research Amgen, Inc.  Thousand Oaks California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9447-3164","authenticated-orcid":false,"given":"Hugo M.","family":"Vargas","sequence":"additional","affiliation":[{"name":"Amgen Research, Translational Safety Research Amgen, Inc.  Thousand Oaks California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"Anonymous \u201cICH S7A: Safety Pharmacology Studies for Human Pharmaceuticals \u201d2000."},{"key":"e_1_2_9_3_1","unstructured":"Anonymous \u201cICH S7B: The Non\u2010Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals \u201d2005."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2009.05.006"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2010.05.011"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2021.107067"},{"key":"e_1_2_9_7_1","unstructured":"Anonymous \u201cICH E14\/S7B Implementation Working Group: Clinical and Nonclinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential\u2014Questions and Answers \u201d2022a."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2023.107265"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2023.107270"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2019.106606"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13103"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3283"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2029"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2137"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-662-46943-9_14"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2022.107247"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-161-40533"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2015.04.007"},{"issue":"4","key":"e_1_2_9_19_1","first-page":"464","article-title":"Comparison of Telemetry and High\u2010Definition Oscillometry for Blood Pressure Measurements in Conscious Dogs: Effects of Torcetrapib","volume":"49","author":"Meyer O.","year":"2010","journal-title":"Journal of the American Association for Laboratory Animal Science"},{"key":"e_1_2_9_20_1","article-title":"Current Practices on the Measurement of Electrocardiogram and Hemodynamic Parameters in Non\u2010Rodent Species in Regulatory Safety Assessment Studies","author":"Jean\u2010Pierre Valentin T. 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