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

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 (Ct(trough)) and total average area under the concentration-time curve (AUCt(ave)) 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(2)lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. RESULTS: AUCt(ave) and Ct(trough) 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(trough), not AUCt(ave), associated significantly with P/F (β=-19,64; p-value=0.014) and O(2)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(trough), but not AUCt(ave) associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Ct(trough) and AUCt(ave), 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. Ct(trough) and AUCt(ave) 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.