{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:44:49Z","timestamp":1770817489853,"version":"3.50.1"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,12,2]],"date-time":"2023-12-02T00:00:00Z","timestamp":1701475200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sparsentan is a dual endothelin\/angiotensin II receptor antagonist indicated to reduce proteinuria in patients with primary IgA nephropathy at high risk of disease progression. In\u00a0vitro data indicate that sparsentan is likely to inhibit or induce various CYP enzymes at therapeutic concentrations. Sparsentan as a victim and perpetrator of CYP3A4 mediated drug\u2013drug interactions (DDIs) has been assessed clinically. A mechanistic, bottom\u2010up, physiologically\u2010based pharmacokinetic (PK) model for sparsentan was developed based on in\u00a0vitro data of drug solubility, formulation dissolution and particle size, drug permeability, inhibition and induction of metabolic enzymes, and P\u2010glycoprotein (P\u2010gp) driven efflux. The model was verified using clinical PK data from healthy adult volunteers administered single and multiple doses in the fasted and fed states for a wide range of sparsentan doses. The model was also verified by simulation of clinically observed DDIs. The verified model was then used to test various DDI simulations of sparsentan as a perpetrator and victim of CYP3A4 using an expanded set of inducers and inhibitors with varying potency. Additional perpetrator and victim DDI simulations were performed using probes for CYP2C9 and CYP2C19. Simulations were conducted to predict the effect of complete inhibition of P\u2010gp inhibition on sparsentan absorption and clearance. The predictive simulations indicated that exposure of sparsentan could increase greater than two\u2010fold if co\u2010administered with a strong CYP3A4 inhibitor, such as itraconazole. Other potential DDI interactions as victim or perpetrator were all within two\u2010fold of control. The effect of complete P\u2010gp inhibition on sparsentan PK was negligible.<\/jats:p>","DOI":"10.1002\/psp4.13086","type":"journal-article","created":{"date-parts":[[2023,12,2]],"date-time":"2023-12-02T17:10:40Z","timestamp":1701537040000},"page":"317-329","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Physiologically\u2010based pharmacokinetic model of sparsentan to evaluate drug\u2013drug interaction potential"],"prefix":"10.1002","volume":"13","author":[{"given":"Nikunjkumar K.","family":"Patel","sequence":"first","affiliation":[{"name":"Simcyp Division Certara UK Limited  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5747-5363","authenticated-orcid":false,"given":"Kuan\u2010Fu","family":"Chen","sequence":"additional","affiliation":[{"name":"Simcyp Division Certara UK Limited  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0754-3716","authenticated-orcid":false,"given":"Shang\u2010Chiung","family":"Chen","sequence":"additional","affiliation":[{"name":"Formerly Travere Therapeutics, Inc.  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San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,12,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.04.026"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1206793"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjms.2020.10.003"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-6386(04)01081-9"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/snep.2003.50025"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2002.00269.x"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2012.58"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1106556"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ackd.2014.05.009"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.05960616"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010040355"},{"issue":"1332","key":"e_1_2_11_13_1","article-title":"Immunoglobulin a nephropathy. 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Guidance for industry.2012https:\/\/pdfs.semanticscholar.org\/3aa6\/c5fa064816cb8525d967be25bd92dfe3444d.pdf?_ga=2.24434686.577539498.1567088324\u201073214531.1567088324Accessed August 29 2019."},{"key":"e_1_2_11_26_1","unstructured":"European Medicines Agency.Guideline on the investigation of drug interactions.2012https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/guideline\u2010investigation\u2010drug\u2010interactions_en.pdfAccessed August 29 2019."},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-017-0976-0"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2018.10.033"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.539"},{"key":"e_1_2_11_30_1","first-page":"51","article-title":"A clinical study assessing potential induction of CYP3A4 and CYP2B6 by steady\u2010state sparsentan (RE\u2010021), a first\u2010in\u2010class, potent, dual angiotensin II blocker and endothelin type A receptor antagonist, using midazolam and bupropion as in\u00a0vivo probes","volume":"6","author":"Karol M, Pan\u2010Zhou X, Leach K,","year":"2017","journal-title":"Clin Pharmacol Drug Develop"},{"key":"e_1_2_11_31_1","unstructured":"U.S. Food and Drug Administration.Clinical drug interaction studies \u2013 cytochrome P450 enzyme\u2010 and transporter\u2010mediated drug interactions: guidance for industry.2020https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/clinical\u2010drug\u2010interaction\u2010studies\u2010cytochrome\u2010p450\u2010enzyme\u2010and\u2010transporter\u2010mediated\u2010drug\u2010interactionsAccessed May 1 2023."},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1013"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.058099"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12070672"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.13086","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T07:28:27Z","timestamp":1707895707000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.13086"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,2]]},"references-count":33,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,2]]}},"alternative-id":["10.1002\/psp4.13086"],"URL":"https:\/\/doi.org\/10.1002\/psp4.13086","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,2]]},"assertion":[{"value":"2023-07-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}