{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:51:39Z","timestamp":1761238299923,"version":"build-2065373602"},"reference-count":17,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2016,7,8]],"date-time":"2016-07-08T00:00:00Z","timestamp":1467936000000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:sec><jats:title>Study Objective<\/jats:title><jats:p>To examine the effect of increased gastric <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content> on exposure to evacetrapib, a cholesteryl ester transfer protein inhibitor evaluated for the treatment of atherosclerotic heart disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Open\u2010label, two\u2010treatment, two\u2010period, fixed\u2010sequence crossover study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Clinical research unit.<\/jats:p><\/jats:sec><jats:sec><jats:title>Subjects<\/jats:title><jats:p>Thirty\u2010four healthy subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Intervention<\/jats:title><jats:p>In period 1, subjects received a single oral dose of evacetrapib 130\u00a0mg on day 1, followed by 7\u00a0days of analysis for evacetrapib plasma concentrations. In period 2, subjects received a once\/day oral dose of omeprazole 40\u00a0mg on days 8\u201320, with a single oral dose of evacetrapib 130\u00a0mg administered 2\u00a0hours after the omeprazole dose on day 14, followed by 7\u00a0days of pharmacokinetic sampling. Subjects were discharged on day 21 and returned for a follow\u2010up visit at least 14\u00a0days after the last dose of evacetrapib in period 2. Gastric <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content> was measured before subjects received each evacetrapib dose.<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements and Main Results<\/jats:title><jats:p>Noncompartmental pharmacokinetic parameters were estimated from plasma concentration\u2013time data and compared between periods 1 and 2. Geometric mean ratios with 90% confidence intervals (<jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>s) were reported. Safety and tolerability were also assessed. The mean age of the 34 subjects was 40.9\u00a0years; mean body mass index was 27.2\u00a0kg\/m<jats:sup>2<\/jats:sup>. Omeprazole treatment increased mean gastric <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content> across all subjects by 2.80 and increased evacetrapib area under the concentration versus time curve from time zero extrapolated to infinity (<jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2013\u221e<\/jats:sub>) and maximum observed drug concentration (C<jats:sub>max<\/jats:sub>) by 15% (90% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content> \u22122 to 35) and 30% (90% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content> 3\u201363), respectively. For both parameters, the upper bound of the 90% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content> of the ratio of geometric least\u2010squares means exceeded 1.25 but was less than 2, indicating a weak interaction. To assess the effect of gastric <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content> on subjects who responded best to omeprazole treatment, the analyses were repeated to include only the 22 subjects whose predose gastric <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content> was 3.0 or lower in period 1 and 4.0 or higher in period 2. In this subpopulation, mean gastric <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content> increased by 4.15 during omeprazole treatment, and evacetrapib <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2013\u221e<\/jats:sub> and C<jats:sub>max<\/jats:sub> increased by 22% (90% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content> 4\u201342) and 35% (90% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content> 1\u201380), respectively. Despite the small mathematical differences between the analyses, the overall effect in both was a minimal increase in evacetrapib exposure. Of 35 adverse events reported during the study, 4 (11.4%) were considered to be treatment\u2010related, and most were mild in severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The impact of increased gastric <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content> on evacetrapib pharmacokinetics would not be expected to be clinically relevant. The magnitude of change in <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content> did not affect the degree of the interaction.<\/jats:p><\/jats:sec>","DOI":"10.1002\/phar.1778","type":"journal-article","created":{"date-parts":[[2016,6,10]],"date-time":"2016-06-10T12:58:38Z","timestamp":1465563518000},"page":"749-756","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Impact of Increased Gastric <scp>pH<\/scp> on the Pharmacokinetics of Evacetrapib in Healthy Subjects"],"prefix":"10.1002","volume":"36","author":[{"given":"David S.","family":"Small","sequence":"first","affiliation":[{"name":"Eli Lilly and Company Indianapolis Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Royalty","sequence":"additional","affiliation":[{"name":"Covance Inc. Evansville Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen A.","family":"Cannady","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Indianapolis Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Hale","sequence":"additional","affiliation":[{"name":"Covance Inc. Madison Wisconsin"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming\u2010Dauh","family":"Wang","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Indianapolis Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delyn","family":"Downs","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Indianapolis Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey G.","family":"Suico","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Indianapolis Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,7,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)61350-5"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(77)90874-9"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-153-12-201012210-00006"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)36957-1"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1009744"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0b013e328353ef1d"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M018069"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.1649"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.12287"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2014.03.045"},{"key":"e_1_2_7_12_1","unstructured":"AstraZeneca Pharmaceuticals LP.Prilosec (omeprazole) package insert.Wilmington DE;2014."},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.179"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1018827003641"},{"key":"e_1_2_7_15_1","unstructured":"FDA Guidance for Industry U.S. Food and Drug Administration.Bioanalytical method validation.2013."},{"key":"e_1_2_7_16_1","unstructured":"EMA Guideline European Medicines Agency Committee for Medicinal Products for Human Use.Guideline on Bioanalytical Method Validation.2011."},{"key":"e_1_2_7_17_1","unstructured":"Eli Lilly and Company.A Bioequivalence Study in Healthy Subjects Administered Evacetrapib Tablets of Varying Tablet Solid Fractions. 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