Population pharmacokinetics of dexamethasone in critically ill COVID-19 patients: Does inflammation play a role?

Abstract

PurposeThe aim of this study is to design a population pharmacokinetic study to gain a deeper understanding of the pharmacokinetics of dexamethasone in critically ill COVID-19 patients in order to identify relevant covariates that can be used to personalize dosing regimens. MethodsBlood samples from critically ill patients receiving fixed-dose intravenous dexamethasone (6 mg/day) for the treatment of COVID-19 were sampled in a retrospective pilot study. The data were analyzed using Nonlinear Mixed Effects Modeling (NONMEM) software for population pharmacokinetic analysis and clinically relevant covariates were selected and evaluated. ResultsA total of 51 dexamethasone samples from 18 patients were analyzed and a two-compartment model fit the data best. The mean population estimates were 2.85 L/h (inter-individual-variability 62.9%) for clearance, 15.4 L for the central volume of distribution, 12.3 L for the peripheral volume of distribution and 2.1 L/h for the inter-compartmental distribution clearance. The covariate analysis showed a significant negative correlation between dexamethasone clearance and CRP. ConclusionsDexamethasone PK parameters in ICU COVID patients were substantially different from those from non-ICU non-COVID patients, and inflammation may play an important role in dexamethasone exposure. This finding suggests that fixed-dose dexamethasone over several days may not be appropriate for ICU COVID patients.