{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T09:51:48Z","timestamp":1791971508348,"version":"4.3.4"},"reference-count":86,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Quantitative systems pharmacology (QSP) integrates mechanistic representations of biology with quantitative pharmacology to support decision\u2011making across the drug development continuum. Over the past two decades, QSP has evolved from an exploratory research activity into an established component of model\u2011informed drug development (MIDD), particularly in settings where system\u2011level interactions complicate the interpretation of exposure\u2013response relationships or where direct clinical data are limited. This review outlines the historical development and conceptual foundations of QSP and summarizes representative clinical applications spanning early, mid, and late development. Examples highlight how QSP is used to support mechanism\u2010based dose and regimen selection, optimization of combination strategies, biomarker\u2011informed patient stratification, and lifecycle management decisions. We also discuss considerations for rigor, credibility, and trustworthiness in alignment with the ICH M15 framework, emphasizing clearly defined questions of interest, context of use, and proportional, decision\u2010driven evaluation of assumptions and uncertainty. Finally, we consider emerging challenges and opportunities for QSP adoption, including reuse of platform models, integration of multi\u2010omics data, and selective incorporation of AI\u2010enabled methods within mechanistically interpretable frameworks.<\/jats:p>","DOI":"10.1002\/jcph.70289","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:09:56Z","timestamp":1789495796000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantitative Systems Pharmacology (QSP): Bridging Biology and Mechanism with Clinical Drug Development Decisions"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7410-6962","authenticated-orcid":false,"given":"Weirong","family":"Wang","sequence":"first","affiliation":[{"name":"Johnson &amp; Johnson  Spring House PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8812-8548","authenticated-orcid":false,"given":"Alexander V.","family":"Ratushny","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Chang","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc.  Research Triangle Park NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yougan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Inc.  Basking Ridge NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqi Q. X.","family":"Gong","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Collegeville PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0898-1750","authenticated-orcid":false,"given":"Abhishek","family":"Gulati","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc.  West Point PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3053-588X","authenticated-orcid":false,"given":"Emma","family":"Hansson","sequence":"additional","affiliation":[{"name":"Pharmetheus AB  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kulesza","sequence":"additional","affiliation":[{"name":"ESQlabs GmbH  Saterland Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7891-5695","authenticated-orcid":false,"given":"Federico","family":"Reali","sequence":"additional","affiliation":[{"name":"Fondazione The Microsoft Research \u2010 University of Trento Center for Computational and Systems Biology  Rovereto Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6330-4129","authenticated-orcid":false,"given":"Conner","family":"Sandefur","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc.  Research Triangle Park NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6015-9636","authenticated-orcid":false,"given":"Brian J.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Madrigal Pharmaceuticals  West Conshohocken PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulya Akpinar","family":"Singh","sequence":"additional","affiliation":[{"name":"Genmab US  Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica E.","family":"Susilo","sequence":"additional","affiliation":[{"name":"Genentech, Inc.  South San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Zaph","sequence":"additional","affiliation":[{"name":"Sanofi  Morristown NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blerta","family":"Shtylla","sequence":"additional","affiliation":[{"name":"Pfizer Inc.  San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/164_2024_733"},{"key":"e_1_2_13_3_1","volume-title":"Quantitative and Systems Pharmacology in the Post\u2010genomic Era: New Approaches to Discovering Drugs and Understanding Therapeutic Mechanisms","author":"Sorger PK","year":"2011"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.47.120505.105154"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-011-0467-9"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.38"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003563"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2009.08.053"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2016.11.001"},{"key":"e_1_2_13_10_1","unstructured":"Food and Drug Administration.Pilot meetings program for model\u2010informed drug development approaches inFed\u00a0Regist.2018;83(74):16868\u201016870."},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.40"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12403"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13208"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-021-00585-x"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12669"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep41231"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12567"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-024-09905-y"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12379"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41540-020-00145-7"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.09.009"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.12.031"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13214"},{"key":"e_1_2_13_24_1","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH M15: Guideline on General Principles for Model\u2010Informed Drug Development.2026."},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12699"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2018.10.033"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00247"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.40"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-013-9297-1"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-44534-2_3"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.528"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1177\/1177625017710941"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-47802-4"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1200"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12426"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-022-09811-1"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/164_2024_734"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1987"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1163432"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13501"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70063"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2023.06.019"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2011.10.001"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.637999"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40495-016-0066-x"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12063"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2018.06.002"},{"key":"e_1_2_13_48_1","first-page":"129","volume-title":"Methods in Molecular Biology","author":"Cheng Y","year":"2022"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12463"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12071"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13270"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40005-025-00791-1"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12636"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41540-024-00355-3"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/immadv\/ltaf001"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaf778"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70041"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12700"},{"key":"e_1_2_13_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3451"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12766"},{"key":"e_1_2_13_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.b.21318"},{"key":"e_1_2_13_62_1","doi-asserted-by":"publisher","DOI":"10.1177\/1087057116635818"},{"key":"e_1_2_13_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-023-09884-6"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3136"},{"key":"e_1_2_13_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-024-00821-1"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3487"},{"key":"e_1_2_13_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-024-01232-9"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41746-024-01188-4"},{"key":"e_1_2_13_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41540-023-00269-6"},{"key":"e_1_2_13_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41540-025-00585-z"},{"key":"e_1_2_13_71_1","unstructured":"ZaphS ShtyllaB ChangS.Best practices on QSP model reporting for regulatory use: perspectives from ISoP QSP SIG Working Group. arXiv.2026: 2604.07811."},{"key":"e_1_2_13_72_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12409"},{"key":"e_1_2_13_73_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12755"},{"key":"e_1_2_13_74_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.20"},{"key":"e_1_2_13_75_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-022-03288-w"},{"key":"e_1_2_13_76_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-023-09871-x"},{"key":"e_1_2_13_77_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-024-09943-6"},{"key":"e_1_2_13_78_1","unstructured":"European Medicines Agency.Model\u2010informed drug development scientific advice and protocol assistance.2026."},{"key":"e_1_2_13_79_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12546"},{"key":"e_1_2_13_80_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0192949"},{"key":"e_1_2_13_81_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12849"},{"key":"e_1_2_13_82_1","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giaa075"},{"key":"e_1_2_13_83_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbae131"},{"key":"e_1_2_13_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-023-00405-9"},{"key":"e_1_2_13_85_1","doi-asserted-by":"publisher","DOI":"10.3389\/fsysb.2024.1380685"},{"key":"e_1_2_13_86_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-025-09984-5"},{"key":"e_1_2_13_87_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70229"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.70289","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcph.70289","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.70289","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T09:20:29Z","timestamp":1791969629000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.70289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":86,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/jcph.70289"],"URL":"https:\/\/doi.org\/10.1002\/jcph.70289","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-05-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70289"}}