{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T21:16:46Z","timestamp":1757452606978},"reference-count":23,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":0,"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":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tolvaptan (TLV) was US Food and Drug Administration (FDA)\u2010approved for the indication to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease in 2018. In vitro, TLV was a breast cancer resistance protein (BCRP) inhibitor, whereas the oxobutyric acid metabolite of TLV (DM\u20104013) was an inhibitor of organic anion transport polypeptide (OATP)1B1 and organic anion transporter (OAT)3. Based on the 2017 FDA guidance, potential for clinically relevant inhibition at these transporters was indicated for the highest TLV regimen. Consequently, two postmarketing clinical trials in healthy subjects were required. In trial 1, 5\u00a0mg rosuvastatin calcium (BCRP and OATP1B1 substrate) was administered alone, with 90\u00a0mg TLV or 48\u00a0h following 7\u00a0days of once daily 300\u00a0mg TLV (i.e., in the presence of DM\u20104103). In trial 2, 40\u00a0mg furosemide (OAT3 substrate) was administered alone and in presence of DM\u20104103. For BCRP, rosuvastatin geometric mean ratios (90% confidence intervals [CIs]) for maximum plasma concentration (C<jats:sub>max<\/jats:sub>) were 1.54 (90% CI 1.26\u20131.88) and for area under the concentration\u2010time curve from time 0 to the time of the last measurable concentration (AUC<jats:sub>t<\/jats:sub>) were 1.69 (90% CI 1.34\u20132.14), indicating no clinically significant interaction. DM\u20104103 produced no clinically meaningful changes in rosuvastatin or furosemide concentrations, indicating no inhibition at OATP1B1 or OAT3. The BCRP prediction assumed the drug dose is completely soluble in 250\u00a0ml; TLV has solubility of ~0.01\u00a0g\/250\u00a0ml. For OATP1B1\/OAT3, if fraction unbound for plasma protein binding (PPB) is less than 1%, then 1% is assumed. DM\u20104103 has PPB greater than 99.8%. Use of actual drug substance solubility and unbound fraction in plasma would have produced predictions consistent with the clinical results.<\/jats:p>","DOI":"10.1111\/cts.13017","type":"journal-article","created":{"date-parts":[[2021,3,20]],"date-time":"2021-03-20T10:32:21Z","timestamp":1616236341000},"page":"1535-1542","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Regulatory guidelines do not accurately predict tolvaptan and metabolite interactions at BCRP, OATP1B1, and OAT3 transporters"],"prefix":"10.1111","volume":"14","author":[{"given":"Susan E.","family":"Shoaf","sequence":"first","affiliation":[{"name":"Quantitative Pharmacology Otsuka Pharmaceutical Development &amp; Commercialization, Inc. Rockville Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Bricmont","sequence":"additional","affiliation":[{"name":"Global Clinical Management Otsuka Pharmaceutical Development &amp; Commercialization, Inc Rockville Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Repella Gordon","sequence":"additional","affiliation":[{"name":"Global Clinical Management Otsuka Pharmaceutical Development &amp; Commercialization, Inc Rockville Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1205511"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710030"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.5414\/CP201621"},{"key":"e_1_2_10_5_1","unstructured":"Australian Government Dept. of Health Therapeutic Goods Administration.Australian Public Assessment Report for Tolvaptan.https:\/\/www.tga.gov.au\/auspar\/auspar\u2010tolvaptan\u20100(2018). Accessed January 20 2021."},{"key":"e_1_2_10_6_1","first-page":"1333","article-title":"Design and evaluation of solid dispersion based tolvaptan immediate release tablets","volume":"4","author":"Magar DD","year":"2014","journal-title":"Indo Am J Pharm Res"},{"key":"e_1_2_10_7_1","first-page":"218","article-title":"Design and evaluation of tolvaptan solid dispersions using hot\u2010melt extrusion and spray drying technique\u2014a comparative study","volume":"7","author":"Ramesh K","year":"2015","journal-title":"Der Pharm Lett"},{"key":"e_1_2_10_8_1","unstructured":"Jynarque (tolvaptan)[US prescribing information] (Otsuka Pharmaceutical Co. Ltd. Tokyo 101\u20108535 Japan 2020).https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2018\/204441lbl.pdf. Accessed January 20 2021."},{"key":"e_1_2_10_9_1","unstructured":"US Food and Drug Administration.In vitro drug interaction studies \u2014 cytochrome P450 enzyme\u2010 and transporter\u2010mediated drug interactions: guidance for industry.https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/vitro\u2010drug\u2010interaction\u2010studies\u2010cytochrome\u2010p450\u2010enzyme\u2010and\u2010transporter\u2010mediated\u2010drug\u2010interactions(January 2020). Silver Spring MD. 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January 20 2021."},{"key":"e_1_2_10_12_1","unstructured":"US Food and Drug Administration.Drug Development and Drug Interactions: Table of Substrates Inhibitors and Inducers.https:\/\/www.fda.gov\/drugs\/drug\u2010interactions\u2010labeling\/drug\u2010development\u2010and\u2010drug\u2010interactions\u2010table\u2010substrates\u2010inhibitors\u2010and\u2010inducers(Content current as of March 2020). 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