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Therapeutic antibodies typically show predictable pharmacokinetics (PK) but can exhibit clearance that decreases over time due to treatment. Moreover, time\u2010dependent changes in clearance are frequently associated with drug response, with larger decreases in clearance and increased exposure seen in patients who respond to treatment. This often confounds traditional ER analysis, as drug response influences exposure rather than the reverse. In this review, we survey published population PK analyses for reported time\u2010dependent drug clearance effects across 158 therapeutic antibodies approved or in regulatory review. We describe the mechanisms by which time\u2010dependent clearance can arise, and evaluate trends in frequency, magnitude, and time scale of changes in clearance with respect to indication, mechanistic interpretation of time\u2010dependence, and PK modeling techniques employed. We discuss the modeling and simulation strategies commonly used to characterize time\u2010dependent clearance, and examples where time\u2010dependent clearance has impeded ER analysis. A case study using population model simulation was explored to interrogate the impact of time\u2010dependent clearance on ER analysis and how it can lead to spurious conclusions. Overall, time\u2010dependent clearance arises frequently among therapeutic antibodies and has spurred erroneous conclusions in ER analysis. Appropriate PK modeling techniques aid in identifying and characterizing temporal shifts in exposure that may impede accurate ER assessment and successful dose optimization.<\/jats:p>","DOI":"10.1111\/cts.13676","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T04:20:29Z","timestamp":1698726029000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["<scp>Time\u2010dependent<\/scp>\n                    clearance can confound\n                    <scp>exposure\u2013response<\/scp>\n                    analysis of therapeutic antibodies: A\u00a0comprehensive review of the current literature"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2274-5607","authenticated-orcid":false,"given":"Jeffrey R.","family":"Proctor","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences The University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1550-5071","authenticated-orcid":false,"given":"Harvey","family":"Wong","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences The University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,14]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.401"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.282542"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1953"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-014-2400-5"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.71.6852"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.309"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12633"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2021-1364"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0415"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12855"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12665"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.656"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12561"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12477"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12558"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9528-y"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13996"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12224"},{"key":"e_1_2_12_20_1","unstructured":"US Food and Drug Administration.Project Optimus: reforming the dose optimization and dose selection paradigm in oncology.2023. 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