Effects of dexamethasone coadministered with oseltamivir on the pharmacokinetics of oseltamivir in healthy volunteers.
OBJECTIVE
Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. It is ingested as an oral prodrug that is rapidly metabolized by carboxylesterase 1 (CES1) to its active form, oseltamivir carboxylate. Dexamethasone is also used in the treatment of acute respiratory distress syndrome, a severe complication of influenza; however, its influence on the pharmacokinetics (PK) of oseltamivir is controversial. The aim of this study was to investigate the effects of coadministering 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. Oseltamivir and oseltamivir carboxylate concentrations in plasma and urine were determined using liquid chromatography-tandem mass spectrometry.


RESULTS
Area under the plasma concentration-time curve (AUC) of oseltamivir and oseltamivir carboxylate decreased after dexamethasone treatment for 6 days. 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). The amount of unchanged oseltamivir excreted in urine increased by 14% after dexamethasone treatments.


CONCLUSIONS
Coadministration of dexamethasone with oseltamivir slightly decreased systemic exposure to oseltamivir and oseltamivir carboxylate in healthy volunteers. This result suggests that CES1 is inhibited by dexamethasone in humans. However, coadministration of oseltamivir and dexamethasone did not appear to have a clinically relevant effect on the PK of oseltamivir; based on these results, dexamethasone can be coadministered with oseltamivir.
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul; Center for Clinical Pharmacology and Biomedical Research Institute, Chonbuk National University Medical School, Jeonju.
Kyungho
K
Jang
Department of Psychiatry; Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, Republic of Korea.
Min-Kyoung
MK
Kim
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul.
Jaeseong
J
Oh
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul.
SeungHwan
S
Lee
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul.
Joo-Youn
JY
Cho
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul.
Kyung-Sang
KS
Yu
Department of Psychiatry.
Tai Kiu
TK
Choi
Department of Psychiatry; Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, Republic of Korea.
Sang-Hyuk
SH
Lee
Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, Republic of Korea.
Kyoung Soo
KS
Lim
D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003907:Dexamethasone / Q000008:administration & dosage* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008875:Middle Aged; D053139:Oseltamivir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000998:Antiviral Agents; D053139:Oseltamivir; D003907:Dexamethasone
ARDS; carboxylesterase; influenza; steroid