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 concen-
trations 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 an-
alyses into unbound imatinib and its main metabolite may better explain exposure-response.