Pharmacokinetics and pharmacodynamics of imatinib in COVID-19 patients

Abstract

Introduction: In the randomised double-blind placebo-controlled CounterCovid study, imatinib reduced mortality in COVID-19 patients. High levels of alpha-1 acid glycoprotein (AAG) were associated with increased total imatinib concentrations in COVID-19 patients.

Aims: We aimed to explore possible relationships between pharmacokinetic(PK) profiles of oral imatinib in COVID-19 patients and pharmacodynamic (PD) outcomes. We hypothesize that high total imatinib concentrations may be associated with improved clinical outcomes in COVID-19 patients, when adjusted for AAG.

Methods: PK profiles were expressed as trough concentration at steady state(Css). PD responses were the ratio between partial oxygen pressure and fraction of inspired oxygen(P/F), WHO ordinal scale for clinical improvement(WHO-score) and oxygen supplementation liberation(O2lib). Linear regression, linear mixed effects models and time-to-event analysis were performed and adjusted for possible confounders.

Results: Individual Css could be determined from 168 patients. Css did associate significantly with P/F (β=-199,42; p-value=0.013) and O2lib (HR 0.75; p-value= 0.021), adjusted for sex, age, neutrophil-lymphocyte ratio, dexamethasone usage, AAG and baseline P/F-and WHO-score. Css did not significantly associate with WHO-score.

Concusion: Higher total exposure following oral imatinib in COVID-19 patients did not associate with improved clinical outcomes. Total Css showed an inverse association with PD-outcomes. This association may be biased by disease-course and variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite at Css may better explain exposure-response associations.