{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T01:21:45Z","timestamp":1773019305962,"version":"3.50.1"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Non\u2010alcoholic fatty liver disease and non\u2010alcoholic steatohepatitis describe a collection of liver conditions characterized by the accumulation of liver fat. Despite biopsy being the reference standard for determining the severity of disease, non\u2010invasive measures such as magnetic resonance imaging proton density fat fraction (MRI\u2010PDFF) and FibroScan\u00ae controlled attenuation parameter (CAP\u2122) can be used to understand longitudinal changes in steatosis. The aim of this work was to describe the exposure\u2013response relationship of ervogastat with or without clesacostat on steatosis, through population pharmacokinetic\/pharmacodynamic (PK\/PD) modeling of both liver fat measurements simultaneously. Population pharmacokinetic and exposure\u2013response models using individual predictions of average concentrations were used to describe ervogastat\/clesacostat PKPD. Due to both liver fat endpoints being continuous\u2010bounded outcomes on different scales, a dynamic transform\u2010both\u2010sides approach was used to link a common latent factor representing liver fat to each endpoint. Simultaneous modeling of both MRI\u2010PDFF and CAP\u2122 was successful with both measurements being adequately described by the model. The clinical trial simulation was able to adequately predict the results of a recent Phase 2 study, where subjects given ervogastat\/clesacostat 300\/10\u2009mg BID for 6\u2009weeks had a LS means and model\u2010predicted median (95% confidence intervals) percent change from baseline MRI\u2010PDFF of \u221245.8% and \u221245.6% (\u221261.6% to \u221231.8%), respectively. Simultaneous modeling of both MRI\u2010PDFF and CAP\u2122 was successful with both measurements being adequately described. By describing the underlying changes of steatosis with a latent variable, this model may be extended to describe biopsy results from future studies.<\/jats:p>","DOI":"10.1002\/psp4.13275","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T12:03:18Z","timestamp":1732104198000},"page":"317-330","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exposure\u2013response modeling of liver fat imaging endpoints in non\u2010alcoholic fatty liver disease populations administered ervogastat alone and co\u2010administered with clesacostat"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1862-5805","authenticated-orcid":false,"given":"Jim H.","family":"Hughes","sequence":"first","affiliation":[{"name":"Pfizer Research and Development  Groton Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0727-4683","authenticated-orcid":false,"given":"Neeta B.","family":"Amin","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3302-8742","authenticated-orcid":false,"given":"Jessica","family":"Wojciechowski","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development  Groton Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoli","family":"Vourvahis","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,11,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021115-105331"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/783976"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31173"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-318813"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40273-022-01140-y"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1479"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31599"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-017-4638-3"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.5812\/hepatmon.15167"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ultrasmedbio.2010.07.005"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29639"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1701329"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.04.031"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(23)00159-0"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(20)31392-1"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1948"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29797"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2021-056159"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.782"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2022.12.008"},{"key":"e_1_2_10_23_1","unstructured":"GastonguayMR.Full covariate models as an alternative to methods relying on statistical significance for inferences about covariate effects: a review of methodology and 42 case studies. Paper Presented at: Population Approach Group Europe; 2011 Jun 7\u201310; Athens Greece. Accessed August 2 2022.https:\/\/www.page\u2010meeting.org\/?abstract=2229"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-19425-7_4"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-015-9460-y"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4155"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-7161(07)27012-9"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-7161(07)27013-0"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12280"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-024-01347-6"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01929-y"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12838"},{"key":"e_1_2_10_33_1","volume-title":"NONMEM User's Guides (1989\u20132017)","author":"Beal SL","year":"2017"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2005.04.005"},{"key":"e_1_2_10_35_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2021"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.14"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9255-z"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2007.12.002"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9542-0"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12611"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26465"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.5152\/tjg.2020.18594"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.21037\/qims-21-227"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.14744\/hf.2020.2020.0023"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12664-019-00991-2"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.12.022"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.14309\/ctg.0000000000000023"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-017-4638-3"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.2214\/AJR.22.27878"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-019-0343-9"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csda.2011.10.005"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.13275","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T19:30:23Z","timestamp":1739302223000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.13275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,20]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1002\/psp4.13275"],"URL":"https:\/\/doi.org\/10.1002\/psp4.13275","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,20]]},"assertion":[{"value":"2024-05-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}