{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:40:00Z","timestamp":1788921600389,"version":"build-2803163510"},"reference-count":31,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["115974"],"award-info":[{"award-number":["115974"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25\u201375\u2009mL\/min\/1.73\u2009m<jats:sup>2<\/jats:sup>, and a urine albumin\u2010to\u2010creatinine ratio of 300\u20135,000\u2009mg\/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin\u20101 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma\u2010concentration time curve from zero to infinity (AUC<jats:sub>0\u2212inf<\/jats:sub>) 41.3\u2009ng\u00b7h\/mL) or slow (atrasentan AUC<jats:sub>0\u2212inf<\/jats:sub> 49.7\u2009ng\u00b7h\/mL, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45\u20130.81) and 1.35 (95% CI: 0.84\u20132.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95\u20134.03, <jats:italic>P<\/jats:italic>\u2010interaction normal phenotype\u00a0=\u00a00.004), and 4.18 (95% CI: 1.37\u201312.7, <jats:italic>P<\/jats:italic>\u2010interaction normal phenotype\u00a0=\u00a00.060), respectively. OATP1B1 gene polymorphisms are associated with significant between\u2010patient variability in atrasentan plasma exposure and long\u2010term efficacy and safety.<\/jats:p>","DOI":"10.1002\/cpt.2721","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T08:38:55Z","timestamp":1658911135000},"page":"1098-1107","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Organic Anion Transporter Gene Variants Associated With Plasma Exposure and Long\u2010Term Response to Atrasentan in Patients With Diabetic Kidney Disease"],"prefix":"10.1111","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1725-9927","authenticated-orcid":false,"given":"J. David","family":"Smeijer","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology University of Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7253-3998","authenticated-orcid":false,"given":"Jeroen V.","family":"Koomen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology University of Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3981-2941","authenticated-orcid":false,"given":"Donald E.","family":"Kohan","sequence":"additional","affiliation":[{"name":"Division of Nephrology University of Utah Health  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J. V.","family":"McMurray","sequence":"additional","affiliation":[{"name":"British Heart Foundation Cardiovascular Research Centre University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1183-1267","authenticated-orcid":false,"given":"George L.","family":"Bakris","sequence":"additional","affiliation":[{"name":"American Society of Hypertension Comprehensive Hypertension Center University of Chicago Medicine and Biological Sciences  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Correa\u2010Rotter","sequence":"additional","affiliation":[{"name":"National Medical Science and Nutrition Institute Salvador Zubir\u00e1n  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3117-7418","authenticated-orcid":false,"given":"Fan\u2010Fan","family":"Hou","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Nanfang Hospital Southern Medical University, National Clinical Research Center for Kidney Disease  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalane W.","family":"Kitzman","sequence":"additional","affiliation":[{"name":"Sections on Cardiovascular Disease and Geriatrics Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Makino","sequence":"additional","affiliation":[{"name":"Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"Mayer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV (Nephrology and Hypertension) Medical University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0823-5440","authenticated-orcid":false,"given":"Michal","family":"Nowicki","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hypertension and Kidney Transplantation Medical University of Lodz  Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlado","family":"Perkovic","sequence":"additional","affiliation":[{"name":"George Institute for Global Health  Newtown New South Wales Australia"},{"name":"University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Rossing","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center  Gentofte Denmark"},{"name":"Department of Clinical Medicine University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheldon","family":"Tobe","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Sunnybrook Health Sciences Centre University of Toronto and the Northern Ontario School of Medicine  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010Henrik","family":"Parving","sequence":"additional","affiliation":[{"name":"Department of Medical Endocrinology Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dick","family":"de Zeeuw","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology University of Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiddo J. 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