Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.

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Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_1F1A8DF39680
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.
Journal
CPT
Author(s)
Bartelink I.H., Bet P.M., Widmer N., Guidi M., Duijvelaar E., Grob B., Honeywell R., Evelo A., Tielbeek IPE, Snape S.D., Hamer H., Decosterd L.A., Jan Bogaard H., Aman J., Swart E.L.
ISSN
2163-8306 (Electronic)
ISSN-L
2163-8306
Publication state
Published
Issued date
2021
Peer-reviewed
Oui
Volume
10
Number
12
Pages
1497-1511
Language
english
Notes
Publication types: Journal Article ; Randomized Controlled Trial
Publication Status: ppublish
Abstract
This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 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 <sub>max</sub> ) and trough concentration (C <sub>trough</sub> ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (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-19 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-19.
Keywords
Acute-Phase Proteins/metabolism, Aged, Aged, 80 and over, COVID-19/blood, COVID-19/drug therapy, Female, Humans, Imatinib Mesylate/blood, Imatinib Mesylate/therapeutic use, Male, Middle Aged, Protein Binding/drug effects, Protein Binding/physiology, Protein Kinase Inhibitors/blood, Protein Kinase Inhibitors/therapeutic use
Pubmed
Web of science
Open Access
Yes
Create date
07/10/2021 8:44
Last modification date
29/01/2023 6:54
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