{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:04:34Z","timestamp":1784851474664,"version":"3.55.0"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,8,6]],"date-time":"2013-08-06T00:00:00Z","timestamp":1375747200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biopharm &amp; Drug Disp"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Tolvaptan is a selective V<jats:sub>2<\/jats:sub>\u2010receptor antagonist used to treat hypervolemic and euvolemic hyponatremia. A population pharmacokinetic (PK) analysis was performed for tolvaptan in NONMEM\u00ae based upon data obtained from three trials conducted in 93 healthy subjects and six trials conducted in 628 congestive heart failure (CHF) patients or 24 hepatic cirrhosis patients receiving oral tolvaptan (5 to 240\u2009mg). A two\u2010compartment model with first\u2010order absorption and elimination best described tolvaptan PK. Relative oral bioavailability was modeled relative to 100% for a 30\u2009mg dose and ranged from 79.4% to 122%. Body weight and the impact of CHF or hepatic cirrhosis relative to healthy subjects were statistically significant (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) predictors of both the apparent oral clearance (<jats:italic>CL<\/jats:italic>\/<jats:italic>F<\/jats:italic>) and apparent central volume of distribution (<jats:italic>V<\/jats:italic><jats:sub>c<\/jats:sub>\/<jats:italic>F<\/jats:italic>). The <jats:italic>CL<\/jats:italic>\/<jats:italic>F<\/jats:italic> was reduced to 58.2% for New York Heart Association (NYHA) Class 1 or 2 CHF, 45.5% for NYHA Class 3 or 4 CHF, and 58.0% for hepatic cirrhosis relative to healthy subjects. <jats:italic>V<\/jats:italic><jats:sub>c<\/jats:sub>\/<jats:italic>F<\/jats:italic> was reduced to 59.9% for NYHA Class 1 or 2 CHF and 51.3% for NYHA Class 3 or 4 CHF, and was 64.8% larger for severe hepatic cirrhosis (Child\u2010Pugh score\u2009\u2265\u200910) relative to healthy subjects. A slight additional decrease in <jats:italic>CL<\/jats:italic>\/<jats:italic>F<\/jats:italic> of 18.3% was also detected for patients with moderate hyponatremia (serum sodium of 115\u2013130\u2009mEq\/l) after adjusting for CHF or cirrhosis (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). This population PK model enabled assessment of tolvaptan PK with varying degrees of CHF and hepatic cirrhosis with fluid overload and may be used to explore PK\u2010PD relationships with respect to fluid and electrolyte balance. Copyright \u00a9 2013 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/bdd.1849","type":"journal-article","created":{"date-parts":[[2013,6,24]],"date-time":"2013-06-24T07:16:39Z","timestamp":1372058199000},"page":"336-347","source":"Crossref","is-referenced-by-count":8,"title":["Population pharmacokinetics of tolvaptan in healthy subjects and patients with hyponatremia secondary to congestive heart failure or hepatic cirrhosis"],"prefix":"10.1002","volume":"34","author":[{"given":"Scott A.","family":"Van Wart","sequence":"first","affiliation":[{"name":"Institute for Clinical Pharmacodynamics  Latham NY USA"},{"name":"Department of Pharmaceutical Sciences, University at Buffalo State University of New York  Buffalo NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan E.","family":"Shoaf","sequence":"additional","affiliation":[{"name":"Otsuka Pharmaceutical Development and Commercialization, Inc.  Rockville MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh","family":"Mallikaarjun","sequence":"additional","affiliation":[{"name":"Otsuka Pharmaceutical Development and Commercialization, Inc.  Rockville MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald E.","family":"Mager","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University at Buffalo State University of New York  Buffalo NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,8,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/CRD.0b013e318190e72c"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.2003.01647.x"},{"issue":"3","key":"e_1_2_8_4_1","first-page":"H396","article-title":"Plasma vasopressin response to osmotic and hemodynamic stimuli in heart failure","volume":"248","author":"Uretsky BF","year":"1985","journal-title":"Am J Physiol"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1996.253"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.emc.2005.03.001"},{"key":"e_1_2_8_7_1","unstructured":"SamscaTM(tolvaptan) tablets [package insert]. 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