Back to Search
Start Over
Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.
- Source :
-
CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2021 Dec; Vol. 10 (12), pp. 1497-1511. Date of Electronic Publication: 2021 Oct 24. - Publication Year :
- 2021
-
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 <subscript>max</subscript> ) and trough concentration (C <subscript>trough</subscript> ) 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.<br /> (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Aged
Aged, 80 and over
Female
Humans
Imatinib Mesylate therapeutic use
Male
Middle Aged
Protein Binding drug effects
Protein Binding physiology
Protein Kinase Inhibitors therapeutic use
Acute-Phase Proteins metabolism
COVID-19 blood
Imatinib Mesylate blood
Protein Kinase Inhibitors blood
COVID-19 Drug Treatment
Subjects
Details
- Language :
- English
- ISSN :
- 2163-8306
- Volume :
- 10
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- CPT: pharmacometrics & systems pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 34608769
- Full Text :
- https://doi.org/10.1002/psp4.12718