Back to Search
Start Over
Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19.
- Source :
-
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2023 May 01; Vol. 184, pp. 106418. Date of Electronic Publication: 2023 Mar 02. - Publication Year :
- 2023
-
Abstract
- Introduction: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations.<br />Aims: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters.<br />Methods: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Ct <subscript>trough</subscript> ) and total average area under the concentration-time curve (AUCt <subscript>ave</subscript> ) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O <subscript>2</subscript> lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders.<br />Results: AUCt <subscript>ave</subscript> and Ct <subscript>trough</subscript> were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Ct <subscript>trough</subscript> , not AUCt <subscript>ave</subscript> , associated significantly with P/F (β=-19,64; p-value=0.014) and O <subscript>2</subscript> lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Ct <subscript>trough</subscript> , but not AUCt <subscript>ave</subscript> associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Ct <subscript>trough</subscript> and AUCt <subscript>ave</subscript> , and PD outcomes.<br />Conclusion: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Ct <subscript>trough</subscript> and AUCt <subscript>ave</subscript> inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.<br />Competing Interests: Declaration of Competing Interest J.A. is an inventor on a patent (WO2012150857A1, 2011) covering protection against endothelial barrier dysfunction through inhibition of the tyrosine kinase abl-related gene (arg). J.A. served as a non-compensated scientific advisor for Exvastat Ltd. S.S. is an employee of Exvastat Ltd. and has no other conflicts of interests. All other authors declare no competing interests.<br /> (Copyright © 2023. Published by Elsevier B.V.)
Details
- Language :
- English
- ISSN :
- 1879-0720
- Volume :
- 184
- Database :
- MEDLINE
- Journal :
- European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 36870577
- Full Text :
- https://doi.org/10.1016/j.ejps.2023.106418