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. Aim(s) We aimed to explore possible relationships between pharmacokinetic(PK) profiles of oral imatinib in COVID19 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. Method(s) 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. Result(s) Individual Css could be determined from 168 patients. Css did associate significantly with P/F (beta=-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.