{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T02:08:34Z","timestamp":1781402914447,"version":"3.54.1"},"reference-count":32,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Following the decade\u2010long clinical investigation, venetoclax has accrued pharmacokinetic (PK) data across multiple populations and widely ranging demographics, intrinsic, and extrinsic factors. We leveraged these rich data to systematically characterize venetoclax PK and assess covariate effects with population PK modeling. Plasma concentration\u2013time data were pooled from 3016 subjects enrolled in 41 phase 1, 2, and 3 clinical studies, including patients from 9 indications and healthy volunteers. A nonlinear mixed\u2010effect model was developed. Covariates were evaluated with full covariate modeling approach. A 2\u2010compartment model with 3 transit absorption compartments described the data well. The impact of moderate and strong cytochrome P450 (CYP) 3A inhibition on apparent clearance (CL\/F), female sex on apparent volume of distribution, food effect on relative bioavailability, and dose nonlinearity was confirmed. Newly identified covariate effects include 48% lower CL\/F in subjects with severe hepatic impairment, 61% higher bioavailability in Asian subjects. When multiple CYP3A inhibitors are taken simultaneously, a 49% decrease in CL\/F was estimated with multiple moderate inhibitors, more substantial than the 22% decrease of a single moderate inhibitor. An 85% decrease in CL\/F was indicated when at least 1 strong CYP3A inhibitor was taken in combination, comparable to that of a single strong inhibitor. A venetoclax cross\u2010indication population PK model with improved absorption\u2010phase characterization was developed. Covariate analyses suggested lower CL\/F for subjects with severe hepatic impairment and higher bioavailability in Asian subjects. Further decrease in CL\/F was indicated when multiple moderate CYP3A inhibitors are present, compared to a single moderate inhibitor.<\/jats:p>","DOI":"10.1002\/jcph.2248","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T04:38:45Z","timestamp":1681447125000},"page":"950-960","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials"],"prefix":"10.1002","volume":"63","author":[{"given":"Jingqi Q. X.","family":"Gong","sequence":"first","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc. North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Suleiman","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Deutschland GmbH &amp; Co. KG  Ludwigshafen am Rhein Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeev","family":"Menon","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc. North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Deng","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech Research and Early Development South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Mensing","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Deutschland GmbH &amp; Co. KG  Ludwigshafen am Rhein Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Hamed","family":"Salem","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc. North Chicago Illinois USA"},{"name":"Clinical Pharmacy Ain Shams University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30525-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/jpm11060463"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-11-880526"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2018-0121"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-4842"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2019.10.005"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26083"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-016-9927-9"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.821"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00788-8"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00746-4"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-020-04179-w"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-018-0793-y"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-007-9066-0"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","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.2011. Abstract 2229 p 20.www.page\u2010meeting.org\/?abstract=2229","DOI":"10.1111\/j.1365-294X.2011.05104.x"},{"issue":"1","key":"e_1_2_10_17_1","article-title":"A full model estimation approach for covariate effects: inference based on clinical importance and estimation precision","volume":"6","author":"Gastonguay MR","year":"2004","journal-title":"AAPS J"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.30.2307"},{"key":"e_1_2_10_19_1","unstructured":"United States Food and Drug Administration.Guidance for industry: pharmacokinetics in patients with impaired renal function\u2014study design data analysis and impact on dosing and labeling.2010. Accessed 18 Feb 2019.http:\/\/www.fda.gov\/downloads\/Drugs\/&\/Guidances\/UCM204959.pdf"},{"key":"e_1_2_10_20_1","unstructured":"United States Food and Drug Administration.Guidance for industry\u2010 pharmacokinetics in patients with impaired hepatic function: study design data analysis and impact on dosing and labeling.2020. Accessed 14 July 2022. Available from:https:\/\/www.fda.gov\/media\/78573\/download"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13577"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-022-01172-4"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.395"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2964"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-016-0453-9"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30012-8"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/17474086.2020.1796620"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020004146"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2005"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.712"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2373"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2646"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2140"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.2248","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T08:28:50Z","timestamp":1692347330000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.2248"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,23]]},"references-count":32,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,8]]}},"alternative-id":["10.1002\/jcph.2248"],"URL":"https:\/\/doi.org\/10.1002\/jcph.2248","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,23]]},"assertion":[{"value":"2022-12-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}