{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T16:55:18Z","timestamp":1781456118973,"version":"3.54.1"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study aimed to develop a pharmacokinetic\/pharmacodynamic model using summary-level data (SLD-PK\/PD model) for ustekinumab in Crohn\u2019s disease and to propose practical considerations and an operating framework for empirical Bayes estimation (EBE) when individual patient data (IPD) models are unavailable.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>An SLD-PK\/PD model was constructed using arm-level Crohn\u2019s Disease Activity Index (CDAI) data from phase IIb\/III trials. To evaluate EBE performance, simulated IPD (simIPD) was generated using a reported IPD-PK\/PD model. Pseudo-SLD was derived from simIPD to refit the SLD-PK\/PD model. EBE was performed at Week 8 to predict CDAI up to Week 20. Because individual-level variability is not identifiable from SLD, uncertainty was propagated using a prespecified \u03c32 grid and \u03c92 scaling, with \u03b7-shrinkage-guided bounds.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>Based on the variance-range framework, patients were classified as consistently predicted remission (6.9%), consistently predicted non-remission (66.2%), or indeterminate (26.9%). Predictive accuracy varied across \u03c32 assumptions, demonstrating the practical impact of variance specification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Although EBE using an SLD-PK\/PD model is practically useful when IPD-PK\/PD models are unavailable, predictions depend on variance assumptions. Therefore, \u03c32 and \u03c92 should be treated as uncertainty ranges, and decision stability should be evaluated across these ranges to ensure robust clinical applications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jpp\/rgag033","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T12:50:36Z","timestamp":1773838236000},"source":"Crossref","is-referenced-by-count":0,"title":["Practical considerations for empirical Bayes estimation using a pharmacokinetic\/pharmacodynamic model developed from summary-level data of ustekinumab therapy in Crohn\u2019s disease"],"prefix":"10.1093","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0425-0205","authenticated-orcid":false,"given":"Koji","family":"Kimura","sequence":"first","affiliation":[{"name":"Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Center for Gastroenterology and Inflammatory Bowel Disease, Ofuna Chuo Hospital , 6-2-24 Ofuna, Kamakura, Kanagawa 247-0056 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"2026061313244812900_ref1","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1146\/annurev-pharmtox-033020-113257","article-title":"Annual review of pharmacology and toxicology: model-informed precision dosing: background, requirements, validation, implementation, and forward trajectory of individualizing drug therapy","volume":"61","author":"Darwich","year":"2021","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"2026061313244812900_ref2","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1002\/cpdd.638","article-title":"Toward dynamic prescribing information: codevelopment of companion model-informed precision dosing tools in drug development","volume":"8","author":"Polasek","year":"2019","journal-title":"Clin Pharmacol Drug Dev"},{"key":"2026061313244812900_ref3","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1002\/cpt.659","article-title":"Why has model-informed precision dosing not yet become common clinical reality? Lessons from the past and a roadmap for the future","volume":"101","author":"Darwich","year":"2017","journal-title":"Clin Pharmacol Ther"},{"key":"2026061313244812900_ref4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2020.105317","article-title":"Prediction of treatment failure during infliximab induction therapy in inflammatory bowel disease patients based on pharmacokinetic and pharmacodynamic modeling","volume":"150","author":"Kimura","year":"2020","journal-title":"Eur J Pharm Sci"},{"key":"2026061313244812900_ref5","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1093\/jpp\/rgae092","article-title":"A prediction method for the individual serum concentration and therapeutic effect for optimizing adalimumab therapy in inflammatory bowel disease","volume":"77","author":"Kimura","year":"2025","journal-title":"J Pharm Pharmacol"},{"key":"2026061313244812900_ref6","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1002\/psp4.12372","article-title":"Model-informed drug discovery and development: current industry good practice and regulatory expectations and future perspectives","volume":"8","author":"Marshall","year":"2019","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2026061313244812900_ref7","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1002\/cpt.1462","article-title":"Model-based meta-analysis: optimizing research, development, and utilization of therapeutics using the totality of evidence","volume":"106","author":"Upreti","year":"2019","journal-title":"Clin Pharmacol Ther"},{"key":"2026061313244812900_ref8","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1002\/psp4.12041","article-title":"The many flavors of model-based meta-analysis: part I\u2014introduction and landmark data","volume":"5","author":"Boucher","year":"2016","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2026061313244812900_ref9","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1002\/psp4.12299","article-title":"Many flavors of model-based meta-analysis: part II\u2014Modeling summary level longitudinal responses","volume":"7","author":"Boucher","year":"2018","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2026061313244812900_ref10","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1182\/bloodadvances.2017013805","article-title":"Model-based meta-analysis to evaluate optimal doses of direct oral factor xa inhibitors in atrial fibrillation patients","volume":"2","author":"Yoshioka","year":"2018","journal-title":"Blood Adv"},{"key":"2026061313244812900_ref11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/psp4.70053","article-title":"Examining the reliability of model-based meta-analysis (MBMA) outcomes: a simulation study","volume":"15","author":"Yu","year":"2025","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2026061313244812900_ref12","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1007\/s10928-017-9529-x","article-title":"Challenges in longitudinal exposure-response modeling of data from complex study designs: a case study of modeling CDAI score for ustekinumab in patients with Crohn\u2019s disease","volume":"44","author":"Hu","year":"2017","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2026061313244812900_ref13","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1016\/J.CLINTHERA.2022.08.010","article-title":"Population pharmacokinetics and exposure\u2013response analyses of ustekinumab in patients with moderately to severely active Crohn\u2019s disease","volume":"44","author":"Adedokun","year":"2022","journal-title":"Clin Ther"},{"key":"2026061313244812900_ref14","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1056\/nejmoa1602773","article-title":"Ustekinumab as induction and maintenance therapy for Crohn\u2019s disease","volume":"375","author":"Feagan","year":"2016","journal-title":"N Engl J Med"},{"key":"2026061313244812900_ref15","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/S0016-5085(76)80163-1","article-title":"Development of a Crohn\u2019s disease activity index: National Cooperative Crohn\u2019s Disease Study","volume":"70","author":"Best","year":"1976","journal-title":"Gastroenterology"},{"key":"2026061313244812900_ref16","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1056\/nejmoa1203572","article-title":"Ustekinumab induction and maintenance therapy in refractory Crohn\u2019s disease","volume":"367","author":"Sandborn","year":"2012","journal-title":"N Engl J Med"},{"key":"2026061313244812900_ref17","author":"Pharmaceuticals and Medical Devices Agency","year":"2017"},{"key":"2026061313244812900_ref18","author":"Pharmaceuticals and Medical Devices Agency","year":"2017"},{"key":"2026061313244812900_ref19","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1002\/PSP4.12422","article-title":"NONMEM tutorial part II: estimation methods and advanced examples","volume":"8","author":"Bauer","year":"2019","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2026061313244812900_ref20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.828219","article-title":"Model-based meta-analysis on the efficacy of biologics and small targeted molecules for Crohn\u2019s disease","volume":"13","author":"Yu","year":"2022","journal-title":"Front Immunol"},{"key":"2026061313244812900_ref21","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1002\/psp4.13088","article-title":"Bayesian estimation in NONMEM","volume":"13","author":"Johnston","year":"2024","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2026061313244812900_ref22","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1214\/20-BA1221","article-title":"Rank-normalization, folding, and localization: an improved R\u02c6 for assessing convergence of MCMC (with discussion)","volume":"16","author":"Vehtarh","year":"2021","journal-title":"Bayesian Anal"},{"key":"2026061313244812900_ref23","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1208\/s12248-009-9133-0","article-title":"Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions","volume":"11","author":"Savic","year":"2009","journal-title":"AAPS J"},{"key":"2026061313244812900_ref24"},{"key":"2026061313244812900_ref25","author":"The YODA"},{"key":"2026061313244812900_ref26"},{"key":"2026061313244812900_ref27","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1007\/S10928-010-9152-6","article-title":"Longitudinal aggregate data model-based meta-analysis with NONMEM: approaches to handling within treatment arm correlation","volume":"37","author":"Ahn","year":"2010","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2026061313244812900_ref28","doi-asserted-by":"publisher","first-page":"e2235060","DOI":"10.1001\/JAMANETWORKOPEN.2022.35060","article-title":"Placebo response to oral administration in osteoarthritis clinical trials and its associated factors: a model-based meta-analysis","volume":"5","author":"Wen","year":"2022","journal-title":"JAMA Netw Open"},{"key":"2026061313244812900_ref29","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1002\/psp4.12078","article-title":"Clinical trial simulations from a model-based meta-analysis of studies in patients with advanced hepatocellular carcinoma receiving antiangiogenic therapy","volume":"5","author":"Zierhut","year":"2016","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2026061313244812900_ref30","doi-asserted-by":"publisher","first-page":"2728","DOI":"10.1016\/j.cgh.2021.10.002","article-title":"Effectiveness of reinduction and\/or dose escalation of ustekinumab in Crohn\u2019s disease: a systematic review and meta-analysis","volume":"20","author":"Meserve","year":"2022","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2026061313244812900_ref31","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1053\/j.gastro.2020.12.031","article-title":"STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD","volume":"160","author":"Turner","year":"2021","journal-title":"Gastroenterology"}],"container-title":["Journal of Pharmacy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/78\/6\/rgag033\/68522066\/rgag033.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/78\/6\/rgag033\/68522066\/rgag033.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T16:09:37Z","timestamp":1781453377000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpp\/article\/doi\/10.1093\/jpp\/rgag033\/8707544"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":31,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6,2]]}},"URL":"https:\/\/doi.org\/10.1093\/jpp\/rgag033","relation":{},"ISSN":["2042-7158"],"issn-type":[{"value":"2042-7158","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,6]]},"published":{"date-parts":[[2026,6]]},"article-number":"rgag033"}}