{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T01:43:37Z","timestamp":1791078217232,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":181,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2008,8]]},"abstract":"<jats:sec><jats:title>Background and purpose:<\/jats:title><jats:p>The effects of dofetilide were studied in monkeys and dogs. Pharmacokinetic data were generated together with the monitoring of cardiovascular changes in order to compare effects relative to human exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach:<\/jats:title><jats:p>Beagle dogs and cynomolgus monkeys were telemetered to collect arterial blood pressure, heart rate and ECG for 6\u2003h after selected oral doses of dofetilide. Pharmacokinetic parameters were determined for each dose.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results:<\/jats:title><jats:p><jats:italic>Dogs<\/jats:italic>: increases in the QT<jats:sub>c<\/jats:sub>interval reached 56\u2003ms in dogs dosed with 0.3\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>of dofetilide. Premature ventricular contractions and right bundle branch block were evident at this dose, without changes in cardiovascular parameters. The mean<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>values were 3.35 and 60.15\u2003ng\u2003mL<jats:sup>\u22121<\/jats:sup>at doses of 0.03 and 0.3\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>, respectively.<jats:italic>Monkeys<\/jats:italic>: increases in QT<jats:sub>c<\/jats:sub>intervals reached 40\u201350\u2003ms after 0.03\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>. T\u2010wave changes were observed after 0.03\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>without changes in cardiovascular parameters. The mean<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>values following oral doses of 0.01 and 0.03\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>were 0.919\u2003ng\u2003mL<jats:sup>\u22121<\/jats:sup>and 1.85\u2003ng\u2003mL<jats:sup>\u22121<\/jats:sup>, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications:<\/jats:title><jats:p>Despite dofetilide exposure comparable to that in humans, QT<jats:sub>c<\/jats:sub>responses in dogs were greater than those reported in humans. A comparable human dose used in the monkey achieved only half of the exposure but was associated with twofold greater increases in QT<jats:sub>c<\/jats:sub>. Our data support the view that safety risk assessments of new drugs in animal models should ensure that the clinical therapeutic range of exposure is achieved and any untoward effects interpreted accordingly.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic>(2008)<jats:bold>154<\/jats:bold>, 1457\u20131464; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/bjp.2008.275\">10.1038\/bjp.2008.275<\/jats:ext-link>; published online 7 July 2008<\/jats:p><\/jats:sec>","DOI":"10.1038\/bjp.2008.275","type":"journal-article","created":{"date-parts":[[2008,7,7]],"date-time":"2008-07-07T10:04:05Z","timestamp":1215425045000},"page":"1457-1464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The cardiovascular and pharmacokinetic profile of dofetilide in conscious telemetered beagle dogs and cynomolgus 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