Effects of multiple dosing of dexamethasone on the pharmacokinetics of oseltamivir through carboxylesterase 1 modulation in healthy volunteers

Abstract

Introduction: Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. Dexamethasone may have beneficial effects in the treatment of acute respiratory distress syndrome, a severe complication of influenza. Carboxylesterase (CES) 1 predominantly converts oseltamivir into its active metabolite, oseltamivir carboxylate, in the liver, and dexamethasone modulates the expression of CES1. However, the effects of dexamethasone on the pharmacokinetics (PK) of oseltamivir remain unclear. The aim of this study was to investigate the effects of co-administration of oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers. Methods: An open-label, two-period, one-sequence, multiple-dose study was conducted in 19 healthy male volunteers. Oseltamivir (75 mg) was orally administered on Day 1 and Day 8, and dexamethasone (1.5 mg) was administered once daily from Day 3 to Day 8. Serial blood and urine samples were collected for PK analysis of oseltamivir and oseltamivir carboxylate on Day 1 and Day 8. In addition, a genotype test was performed on Day 1 to identify the CES1 genotype. Oseltamivir and oseltamivir carboxylate concentrations in plasma and urine were determined using liquid chromatography–tandem mass spectrometry. Results: After dexamethasone treatment for 6 days, the area under the plasma concentration–time curve (AUC) of oseltamivir and oseltamivir carboxylate decreased by 4% (P = 0.21) and 12% (P < 0.0001), respectively. The geometric mean ratio (90% confidence interval) of the metabolic ratio (oseltamivir carboxylate AUC0–48h/oseltamivir AUC0–48h) was 0.92 (0.87–0.97

P = 0.02). The amount of unchanged oseltamivir excreted in urine increased by 14% after dexamethasone treatment (P = 0.08). Conclusions: These findings suggest that the co-administration of low-dose dexamethasone and oseltamivir may decrease the systemic exposure to oseltamivir and oseltamivir carboxylate by the inhibition of CES1. However, the co-administration does not appear to have a clinically relevant effect on the PK of oseltamivir. Therefore, low-dose dexamethasone can be co-administered with oseltamivir without dose adjustment.