{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T21:16:17Z","timestamp":1789852577647,"version":"4.0.1"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,3,5]],"date-time":"2016-03-05T00:00:00Z","timestamp":1457136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The purpose was to determine the exposure\u2212response relationship of everolimus in patients with angiomyolipoma from the EXIST\u20102 trial and to analyze the correlation between exposure and plasma concentrations of angiogenic biomarkers in these patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>One hundred and eighteen patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2\u00a0:\u00a01 to receive everolimus 10\u00a0mg (<jats:italic>n<\/jats:italic>\u00a0=\u00a079) or placebo (<jats:italic>n<\/jats:italic>\u00a0=\u00a039) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24 and 48 during double\u2010blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48 and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumour growth were determined by enzyme\u2010linked immunosorbent assay (ELISA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24\u00a0weeks of treatment, reduction of vascular endothelial growth factor D (VEGF\u2010D) and collagen type IV (COL\u2010IV) (mean fold\u2010changes with 95% confidence intervals [CI] were 0.36 [0.33, 0.40], and 0.54 [0.51, 0.57], respectively, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001 for both), along with increased VEGF\u2010A (mean fold\u2010change of 1.59 [1.39, 1.80], <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), were seen. Furthermore, baseline VEGF\u2010D and COL\u2010IV levels were associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12834","type":"journal-article","created":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T21:40:32Z","timestamp":1447882832000},"page":"958-970","source":"Crossref","is-referenced-by-count":26,"title":["Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis"],"prefix":"10.1111","volume":"81","author":[{"given":"Klemens","family":"Budde","sequence":"first","affiliation":[{"name":"Charit\u00e9 Universit\u00e4tsmedizin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard A.","family":"Zonnenberg","sequence":"additional","affiliation":[{"name":"Universitair Medisch Centrum  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Frost","sequence":"additional","affiliation":[{"name":"Minnesota Epilepsy Group  St Paul Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing","family":"Cheung","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shweta","family":"Urva","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Brechenmacher","sequence":"additional","affiliation":[{"name":"Novartis Pharma Corporation  S.A.S. Rueil\u2010Malmaison France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Stein","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Chen","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Christopher","family":"Kingswood","sequence":"additional","affiliation":[{"name":"Royal Sussex County Hospital  Brighton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Bissler","sequence":"additional","affiliation":[{"name":"Lebonheur Children's Hospital and the University of Tennessee  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,3,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20080281"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2011.10.013"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra055323"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61279-9"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1269906"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1159\/000320891"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00569.2013"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2251011477"},{"key":"e_1_2_9_10_1","first-page":"21","article-title":"Angiomyolipoma of kidney","volume":"15","author":"Eble JN","year":"1998","journal-title":"Semin Diagn Pathol"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00838.x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.12-2813"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.07-0898"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.164.4.2011025"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.4065\/75.6.591"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.11.6085"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-014-0151-3"},{"key":"e_1_2_9_18_1","first-page":"5173","article-title":"Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin","volume":"63","author":"El\u2010Hashemite N","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.10.088"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2006.4.143"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61767-X"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023379"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2012.10.006"},{"key":"e_1_2_9_24_1","doi-asserted-by":"crossref","unstructured":"BisslerJJ KingswoodJC RadzikowskaE ZonnenbergBA FrostM BelousovaE SouterM NonomuraN BrakemeierS deVriesPJ BerkowitzN SegalS AnakO PeyrardS BuddeK. 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