Dexamethasone exposure in normal‐weight and obese hospitalized COVID‐19 patients: An observational exploratory trial

Abstract

During the latest pandemic, the RECOVERY study showed the benefits of dexamethasone (DEX) use in COVID-19 patients. Obesity has been proven to be an independent risk factor for severe forms of infection, but little information is available in the literature regarding DEX dose adjustment according to body weight.We conducted a prospective, observational, exploratory study at Geneva University Hospitals to assess the impact of weight on DEX pharmacokinetics (PK) in normalweight versus obese COVID-19 hospitalized patients. Two groups of patients were enrolled: normal-weight and obese (body mass index [BMI] 18.5-25 and >30 kg/ m 2 , respectively). All patients received the standard of care therapy of 6 mg DEX orally. Blood samples were collected, and DEX concentrations were measured.The mean DEX AUC 0-8 and C max were lower in the obese compared to the normalweight group (572.02 ± 258.96 vs. 926.92 ± 552.12 ng h/ml and 138.67 ± 68.03 vs.203.44 ± 126.30 ng/ml, respectively). A decrease in DEX AUC 0-8 of 4% per additional BMI unit was observed, defining a significant relationship between weight and DEX AUC 0-8 (p = 0.004, 95% CI 2-7%). In women, irrespective of the BMI, DEX AUC 0-8 increased by 214% in comparison to men (p < 0.001, 95% CI 154-298%).Similarly, the mean C max increased by 205% in women (p < 0.001, 95% CI 141-297%).Conversely, no significant difference between the obese and normal-weight groups was observed for exploratory treatment outcomes, such as the length of hospitalization. BMI, weight, and gender significantly affected DEX AUC. We conclude that dose adjustment would be needed if the aim is to achieve the same exposures in normal-weight and obese patients. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?COVID-19 is a disease caused by SARS-CoV-2 virus capable of causing mild to severe infections in humans up to pneumonia and acute respiratory distress

Pharmacokinetic/Pharmacodynamic Modeling of Dexamethasone Anti-Inflammatory and Immunomodulatory Effects in LPS-Challenged Rats: A Model for Cytokine Release Syndrome

“…DEX once a day at an oral dose of 6 mg for up to 10 days is a recommended dosing regimen for treatment of COVID-19 patients requiring mechanical ventilation. A clinical trial found mean concentrations achieved in the blood of COVID-19 patients upon single oral administration of DEX at a dose of 6 mg were far above IC 50 values of inhibition of TNFα, IL-6, and NO production estimated in this study (Abouir et al, 2022). In that clinical trial, the mean blood concentration of DEX at 8 h was around 74 29 ng•mL -1 in normal-weight patients.…”

Anti‐inflammatory effects of dexamethasone in COVID‐19 patients: Translational population PK/PD modeling and simulation

“…The metabolism of DEX is through CYP3A4‐mediated hydroxylation 21 . The pro‐inflammatory cytokines, including IL‐6 and TNFα strongly decrease mRNA expression and enzyme activity of CYP enzymes including CYP3A4 in human hepatocytes 22,23,38 . However, our simulations (Figure 4) show no substantial risk of DEX accumulation, even at the highest dose of 12 mg daily for 10 days.…”

“…The PKs of DEX among hospitalized patients with COVID‐19 was assessed without evaluation of potential influences of covariates, such as weight or sex or disease severity. The source publication lacked this information for individual patients 23 . However, our approach was sufficient to allow simulations of DEX concentration‐time profiles in patients with COVID‐19.…”

“…However, our simulations (Figure 4) show no substantial risk of DEX accumulation, even at the highest dose of 12 mg daily for 10 days. Moreover, an increase in DEX dose may be required in obese patients, because a decrease in DEX area under the curve of 4% per body mass index (BMI) unit was observed in patients with COVID‐19 23 . Our PopPK/PD model could be used to assess the potential impact of covariates such as weight or BMI on the PKs and PDs of DEX.…”

“…Blood PK data of DEX in hospitalized patients with COVID‐19 were provided in the supplementary materials of Abouir et al 23 based on a clinical trial (http://clinicaltrials.gov Identifier: NCT04996784). The trial was a prospective, observational, exploratory PK study conducted at Geneva University Hospitals in Switzerland.…”