{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T03:38:58Z","timestamp":1791689938411,"version":"4.3.4"},"reference-count":18,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,2,11]],"date-time":"2024-02-11T00:00:00Z","timestamp":1707609600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004328","name":"Genentech","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Personalized dosing approaches play important roles in clinical practices to improve benefit: risk profiles. Whereas this is also important for drug development, especially in the context of drugs with narrow therapeutic windows, such approaches have not been fully evaluated during clinical development. Fazpilodemab (BFKB8488A) is an agonistic bispecific antibody which was being developed for the treatment of nonalcoholic steatohepatitis. The objective of this study was to characterize the exposure\u2010response relationships of fazpilodemab with the purpose of guiding dose selection for a phase II study, as well as to evaluate various personalized dosing strategies to optimize the treatment benefit. Fazpilodemab exhibited clear exposure\u2010response relationships for a pharmacodynamic (PD) biomarker and gastrointestinal adverse events (GIAEs), such as nausea and vomiting. Static exposure\u2010response analysis, as well as longitudinal adverse event (AE) analysis using discrete\u2010time Markov model, were performed to characterize the observations. Clinical trial simulations were performed based on the developed exposure\u2010response models to evaluate probability of achieving target PD response and the frequency of GIAEs to inform phase II dose selection. Dynamic simulation of personalized dosing strategies demonstrated that the AE\u2010based personalized dosing is the most effective approach for optimizing the benefit\u2013risk profiles. The approach presented here can be a useful framework for quantifying the benefit of personalized dosing for drugs with narrow therapeutic windows.<\/jats:p>","DOI":"10.1002\/psp4.13111","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T05:39:37Z","timestamp":1707716377000},"page":"544-550","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Simulation\u2010based evaluation of personalized dosing approaches for <scp>anti\u2010FGFR<\/scp>\/<scp>KLB<\/scp> bispecific antibody fazpilodemab"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4967-3831","authenticated-orcid":false,"given":"Kenta","family":"Yoshida","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Genentech Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Poon","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajit","family":"Dash","sequence":"additional","affiliation":[{"name":"Early Development Safety Genentech Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Kunder","sequence":"additional","affiliation":[{"name":"Early Clinical Development Genentech Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3127-6758","authenticated-orcid":false,"given":"Leslie","family":"Chinn","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1261-0354","authenticated-orcid":false,"given":"Matts","family":"K\u00e5gedal","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech\u2010Roche  Solna Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,11]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"1","article-title":"Model\u2010informed precision dosing: background, requirements, validation, implementation, and forward trajectory of individualizing drug therapy","volume":"61","author":"Darwich AS","year":"2020","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1830"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(14)70036-2"},{"key":"e_1_2_9_5_1","first-page":"1","article-title":"Precision medicine is not just genomics: the right dose for every patient","volume":"58","author":"Peck R","year":"2017","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1679"},{"key":"e_1_2_9_7_1","unstructured":"Drug Development for Patients \u2010 10 Where Does Precision Medicine And Personalised Medicine Fit In?https:\/\/www.alanmaloney.com\/ch10.html. Accessed December 11 2023."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13027"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13056"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14050"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2015.05.028"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32742"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000002480"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2020.08.061"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29797"},{"key":"e_1_2_9_16_1","unstructured":"Study Details | A multiple ascending dose study to evaluate safety and tolerability of BFKB8488A in participants with type 2 diabetes mellitus and participants with non\u2010alcoholic fatty liver disease | ClinicalTrials.Gov.https:\/\/clinicaltrials.gov\/study\/NCT03060538. Accessed December 9 2023."},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2000.108669"},{"key":"e_1_2_9_18_1","unstructured":"Study Details | A study to evaluate the efficacy safety and pharmacokinetics of BFKB8488A compared with placebo in participants with non\u2010alcoholic Steatohepatitis | ClinicalTrials.Gov.https:\/\/clinicaltrials.gov\/study\/NCT04171765. Accessed December 9 2023"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.4155\/ipk-2017-0011"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.13111","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,13]],"date-time":"2024-04-13T05:41:24Z","timestamp":1712986884000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.13111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,11]]},"references-count":18,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1002\/psp4.13111"],"URL":"https:\/\/doi.org\/10.1002\/psp4.13111","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,11]]},"assertion":[{"value":"2023-11-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}