{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:11:31Z","timestamp":1770898291222,"version":"3.50.1"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:p>\n                    Aldosterone is a mineralocorticoid hormone essential for regulating renal function and blood pressure. Despite its clinical relevance, key aspects of aldosterone pharmacokinetics (PK) and physiological dynamics remain incompletely understood. In serial stages, we developed a semi\u2010mechanistic pharmacokinetic\u2013pharmacodynamic (PK\u2010PD) model to characterize aldosterone dynamics under conditions of circadian production and inhibition by lorundrostat, a selective aldosterone synthase inhibitor. Lorundrostat PK from published single\u2010 and multiple\u2010dose studies in healthy subjects was modeled using a linear hybrid two\u2010compartment model (2CM) with food\u2010dependent absorption and adrenal distribution. Separate assessment of aldosterone PK yielded 2CM properties that were used in defining both the circadian production and adrenal suppression by lorundrostat. Aldosterone concentrations from 24\u2010hour pre\u2010dose phases were characterized with dual harmonic circadian functions with fasting\u2010induced shifts in the timing and amplitude of hormone production. Lorundrostat suppression of aldosterone production was fitted with an extended indirect response model utilizing both the circadian production and 2CM aldosterone PK. Synthesis inhibition was about 90% while IC\n                    <jats:sub>50<\/jats:sub>\n                    values were attained at low doses. Such inhibition induced gradual compensatory increases in plasma renin activity, with rebound effects on aldosterone expected after 7\u2009days of dosing and later. Sensitivity analysis supported the determinants of aldosterone dynamics in the model. This model provides a systems\u2010level framework to disentangle physiological and pharmacological drivers of aldosterone regulation, supports trial design for aldosterone synthase inhibitors, and may inform the development of more complex models for RAAS control of renal and cardiovascular function.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70114","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T12:59:48Z","timestamp":1762347588000},"page":"414-426","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Insights Into Aldosterone Regulation Through Pharmacokinetic\u2013Pharmacodynamic Modeling of an Aldosterone Synthase Inhibitor"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1501-8081","authenticated-orcid":false,"given":"Javiera","family":"Cort\u00e9s\u2010R\u00edos","sequence":"first","affiliation":[{"name":"Division of Pharmacokinetics, Pharmacodynamics and Systems Pharmacology, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences State University of New York  Buffalo New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4027-0550","authenticated-orcid":false,"given":"William J.","family":"Jusko","sequence":"additional","affiliation":[{"name":"Division of Pharmacokinetics, Pharmacodynamics and Systems Pharmacology, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences State University of New York  Buffalo New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"e_1_2_11_1_1","first-page":"361","volume-title":"Vitamins and Hormones","author":"Young M.J.","year":"2019"},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2014.tb00565.x"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2011.07.034"},{"key":"e_1_2_11_4_1","volume-title":"StatPearls","author":"Fountain J.H.","year":"2025"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-14-0537"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2009.03469.x"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.1987.tb02948.x"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004872-199001000-00013"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3109\/07420528509055889"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1999.276.1.E43"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/hr.2016.91"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.121.14519"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjhyper.2004.08.025"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.70000"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-025-03838-0"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41440-022-01009-9"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00419.2023"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae823"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1097968"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.030142"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.116.07716"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41440-022-01070-4"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-014-0340-9"},{"key":"e_1_2_11_24_1","unstructured":"Rohatgi A.WebPlotDigitizer<https:\/\/automeris.io> WebPlotDigitizer\/citation. html (2024)."},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/074823379701300401"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2025.103719"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2501440"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI105149"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0029-1211002"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2010.03897.x"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1991.tb01906.x"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4731(82)90166-2"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020266"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-895X(25)10446-X"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00958.x"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3109\/07420528709078531"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs0390437"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00611.2003"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/hr.2016.166"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.536146"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41440-022-00913-4"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncpneph0575"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02353483"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-023-03566-6"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.23590"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-024-02908-1"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01466736"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1472-8206.1996.tb00603.x"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/js980171q"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2013.00004"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70114","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70114","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70114","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T11:15:47Z","timestamp":1770894947000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,5]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/cpt.70114"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70114","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,5]]},"assertion":[{"value":"2025-07-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}