Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19

Autor: Nadia Baalbaki, Erik Duijvelaar, Medhat M. Said, Job Schippers, Pierre M. Bet, Jos Twisk, Sarah Fritchley, Cristina Longo, Kazien Mahmoud, Anke H. Maitland-van der Zee, Harm Jan Bogaard, Eleonora L. Swart, Jurjan Aman, Imke H. Bartelink
Přispěvatelé: Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Clinical pharmacology and pharmacy, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Epidemiology and Data Science, APH - Health Behaviors & Chronic Diseases, APH - Methodology, AII - Cancer immunology, CCA - Cancer Treatment and quality of life, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Baalbaki, N, Duijvelaar, E, Said, M M, Schippers, J, Bet, P M, Twisk, J, Fritchley, S, Longo, C, Mahmoud, K, Maitland-van der Zee, A H, Bogaard, H J, Swart, E L, Aman, J & Bartelink, I H 2023, ' Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19 ', European Journal of Pharmaceutical Sciences, vol. 184, 106418 . https://doi.org/10.1016/j.ejps.2023.106418
European Journal of Pharmaceutical Sciences, 184:106418. Elsevier
ISSN: 0928-0987
DOI: 10.1016/j.ejps.2023.106418
Popis: 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. 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. 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 (Cttrough) and total average area under the concentration-time curve (AUCtave) 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 (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. Results: AUCtave and Cttrough 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. Cttrough, not AUCtave, associated significantly with P/F (β=-19,64; p-value=0.014) and O2lib (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. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. 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. Cttrough and AUCtave 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.
Databáze: OpenAIRE
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