{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:28:10Z","timestamp":1790926090068,"version":"4.1.0"},"reference-count":0,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2002,6,17]],"date-time":"2002-06-17T00:00:00Z","timestamp":1024272000000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2002,6]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Cariporide (HOE642) is a recently developed inhibitor of the myocardial sodium\u2010hydrogen exchange system. The clinical effects of sodium\u2010hydrogen exchange inhibition in patients at high risk for myocardial cell necrosis were investigated in the GUARDIAN trial (n = 11,590 patients). Although the trial did not show a significant benefit of cariporide over placebo in the overall population, a 25% relative risk reduction in the primary end point of death or myocardial infarction (12.1% for the highest tested cariporide dose of 120 mg 3 times a day versus 16.2% for placebo; <jats:italic>P<\/jats:italic> = .03) was observed in the subpopulation of patients who underwent bypass surgery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>Our objective was to identify an optimal dosing regimen that might offer increased protection during the period of highest risk.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A population pharmacokinetic model of cariporide was developed with use of data from phase I studies. After adequate predictability was shown for the patients in the pharmacokinetic substudy of the GUARDIAN trial (n = 269 patients), the model was used to predict the individual pharmacokinetic profile in the remaining patients. These predicted concentrations were used to calculate the mean concentration during the period of coronary artery bypass graft surgery (the acute risk period in patients who receive coronary artery bypass grafts), and this mean concentration was used as predictor variable in a time\u2010to\u2010event analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A mixture of two Weibull functions adequately described the time course of the observed sum of the acute and chronic hazard rate. The calculated mean concentration during the period of surgery was an adequate predictor for the probability of an event in the acute risk period. The estimated minimal effective mean concentration was 0.5 mg\/L.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A dosing regimen with a loading dose of an infusion of 120 mg\/h for 1 hour followed by an infusion of 20 mg\/h for 47 hours should achieve stable exposure above the estimated minimal effective concentration in more than 95% of patients during and after coronary artery bypass graft surgery.<\/jats:p><jats:p><jats:italic>Clinical Pharmacology &amp; Therapeutics<\/jats:italic> (2002) <jats:bold>71<\/jats:bold>, 457\u2013467; doi: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1067\/mcp.2002.124078\">10.1067\/mcp.2002.124078<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1067\/mcp.2002.124078","type":"journal-article","created":{"date-parts":[[2002,10,9]],"date-time":"2002-10-09T21:24:11Z","timestamp":1034198651000},"page":"457-467","source":"Crossref","is-referenced-by-count":10,"title":["Lessons learned from a phase III population pharmacokinetic study of cariporide in coronary artery bypass graft surgery"],"prefix":"10.1111","volume":"71","author":[{"given":"Willi","family":"Weber","sequence":"first","affiliation":[{"name":"Aventis Pharma Deutschland GmbH, Frankfurt am Main, and Aventis Pharma Inc  Bridgewater"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutz","family":"Harnisch","sequence":"additional","affiliation":[{"name":"Aventis Pharma Deutschland GmbH, Frankfurt am Main, and Aventis Pharma Inc  Bridgewater"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Jessel","sequence":"additional","affiliation":[{"name":"Aventis Pharma Deutschland GmbH, Frankfurt am Main, and Aventis Pharma Inc  Bridgewater"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2002,6,17]]},"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1067\/mcp.2002.124078","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T08:50:38Z","timestamp":1700297438000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1067\/mcp.2002.124078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,6]]},"references-count":0,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2002,6]]}},"alternative-id":["10.1067\/mcp.2002.124078"],"URL":"https:\/\/doi.org\/10.1067\/mcp.2002.124078","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,6]]}}}