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Orally administered amodiaquine is largely converted to the active metabolite desethylamodiaquine. Amodiaquine can cause bradycardia, hypotension, and electrocardiograph QT interval prolongation, but the relationship of these changes to drug concentrations is not well characterized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a secondary analysis of a pharmacokinetic study of the cardiac safety of amodiaquine (10\u00a0mg base\/kg\/day over 3\u00a0days) in 54 Kenyan adults (\u226518\u2009years) with uncomplicated malaria. Nonlinear mixed effects modelling was used to assess amodiaquine and desethylamodiaquine concentration\u2013effect relationships for vital sign (pulse rate, blood pressure) and electrocardiograph interval (QT, QRS, PR) outcomes. We also measured the spontaneous beating heart rate after cumulative dosing of amodiaquine and desethylamodiaquine in isolated mouse atrial preparations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Amodiaquine and desethylamodiaquine caused concentration\u2010dependent mean decreases in pulse rate (1.9 beats\/min per 100\u2009nmol\/L; 95% confidence interval: 1.5\u20132.4), supine systolic blood pressure (1.7\u00a0mmHg per 100\u2009nmol\/L; 1.2\u20132.1), erect systolic blood pressure (1.5\u00a0mmHg per 100\u2009nmol\/L; 1.0\u20132.0) and erect diastolic blood pressure (1.4\u00a0mmHg per 100\u2009nmol\/L; 1.0\u20131.7). The mean QT interval prolongation was 1.4\u2009ms per 100\u2009nmol\/L irrespective of correction factor after adjustment for residual heart rate dependency. There was no significant effect of drug concentration on postural change in blood pressure or PR and QRS intervals. In mouse atria, the spontaneous beating rate was significantly reduced by amodiaquine (<jats:italic>n<\/jats:italic>\u00a0=\u20096) and desethylamodiaquine (<jats:italic>n<\/jats:italic>\u00a0=\u20098) at 3\u00a0\u03bcmol\/L (amodiaquine: 10\u00a0\u00b1\u00a02%; desethylamodiaquine: 12\u2009\u00b1\u00a03%) and 10\u00a0\u03bcmol\/L (amodiaquine: 50\u2009\u00b1\u00a07%; desethylamodiaquine: 46\u2009\u00b1\u00a06%) concentrations with no significant difference in potency between the 2 compounds.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Amodiaquine and desethylamodiaquine have concentration\u2010dependent effects on heart rate, blood pressure, and ventricular repolarization.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15569","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T15:58:08Z","timestamp":1666108688000},"page":"1176-1186","source":"Crossref","is-referenced-by-count":4,"title":["Cardiovascular concentration\u2013effect relationships of amodiaquine and its metabolite desethylamodiaquine: Clinical and preclinical studies"],"prefix":"10.1111","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9941-6975","authenticated-orcid":false,"given":"Xin Hui S.","family":"Chan","sequence":"first","affiliation":[{"name":"Mahidol\u2010Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University  Bangkok Thailand"},{"name":"Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3839-9777","authenticated-orcid":false,"given":"Palang","family":"Chotsiri","sequence":"additional","affiliation":[{"name":"Mahidol\u2010Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University  Bangkok Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca A.","family":"Capel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Pike","sequence":"additional","affiliation":[{"name":"Mahidol\u2010Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University  Bangkok Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borimas","family":"Hanboonkunupakarn","sequence":"additional","affiliation":[{"name":"Mahidol\u2010Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University  Bangkok Thailand"},{"name":"Department of Clinical Tropical Medicine, Faculty of Tropical Medicine Mahidol University  Bangkok Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sue J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Mahidol\u2010Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University  Bangkok Thailand"},{"name":"Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryam","family":"Hanafiah","sequence":"additional","affiliation":[{"name":"Mahidol\u2010Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University  Bangkok Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan Naung","family":"Win","sequence":"additional","affiliation":[{"name":"Mahidol\u2010Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University  Bangkok Thailand"},{"name":"Department of Preventive and Social Medicine University of Medicine  Taunggyi Myanmar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maegan A.","family":"Cremer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean\u2010Ren\u00e9","family":"Kiechel","sequence":"additional","affiliation":[{"name":"Drug for Neglected Diseases Initiative  Geneva Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernhards","family":"Ogutu","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute  Kisumu Kenya"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter R. 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