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Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID\u201019 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (C<jats:sub>max<\/jats:sub>) and trough concentration (C<jats:sub>trough<\/jats:sub>) were 2.32\u2010fold (95% confidence interval [CI] 1.34\u20133.29), 2.31\u2010fold (95% CI 1.33\u20133.29), and 2.32\u2010fold (95% CI 1.11\u20133.53) lower, respectively, for patients with CML\/GIST compared with patients with COVID\u201019, whereas unbound concentrations were comparable among groups. Inclusion of alpha1\u2010acid glycoprotein (AAG) concentrations measured in patients with COVID\u201019 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG\u2010PK\u2010Model) gave an estimated mean (SD) prediction error (PE) of \u221220% (31%) for total and \u22127.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID\u201019 compared to CML\/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID\u201019.<\/jats:p>","DOI":"10.1002\/psp4.12718","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T19:01:44Z","timestamp":1633546904000},"page":"1497-1511","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Elevated acute phase proteins affect pharmacokinetics in COVID\u201019 trials: Lessons from the CounterCOVID \u2010 imatinib study"],"prefix":"10.1002","volume":"10","author":[{"given":"Imke H.","family":"Bartelink","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC, location VUmc Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre M.","family":"Bet","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC, location VUmc Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Widmer","sequence":"additional","affiliation":[{"name":"Service of Clinical Pharmacology Lausanne University Hospital and University of Lausanne Lausanne Switzerland"},{"name":"Specialised Centre for Emergency and Disaster Pharmacy Institute of Pharmaceutical Sciences of Western Switzerland University of Geneva Geneva Switzerland"},{"name":"Pharmacy of the Eastern Vaud Hospitals Rennaz Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monia","family":"Guidi","sequence":"additional","affiliation":[{"name":"Service of Clinical Pharmacology Lausanne University Hospital and University of Lausanne Lausanne Switzerland"},{"name":"Center for Research and Innovation in Clinical Pharmaceutical Sciences Lausanne University Hospital and University of Lausanne Lausanne Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"Duijvelaar","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine Amsterdam Cardiovascular Sciences Amsterdam UMC, location VUmc Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bram","family":"Grob","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC, location VUmc Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Honeywell","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC, location VUmc Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Evelo","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC, location VUmc Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivo P. 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