Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (2003) 74, 17–24; doi: 10.1016/S0009-9236(03)00066-3
Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone*
Jacqueline B. McCrea PharmD1, Anup K. Majumdar PhD1, Michael R. Goldberg MD1, Marian Iwamoto MD1, Cynthia Gargano MS1, Deborah L. Panebianco MS1, Michael Hesney MS1, Christopher R. Lines PhD1, Kevin J. Petty MD1, Paul J. Deutsch MD1, M. Gail Murphy MD1, Keith M. Gottesdiener MD1, D. Ronald Goldwater MD1 and Robert A. Blum PharmD1
1Merck Research Laboratories, Blue Bell, PharmaKinetics Laboratories, Baltimore, and Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, Buffalo, NY, USA
Correspondence: Christopher R. Lines, PhD, Merck Research Laboratories, 10 Sentry Pkwy, Blue Bell, PA 19422, USA. E-mail: chris_lines@merck.com
*Funded by Merck & Co, Inc.
Received 22 November 2002; Accepted 27 February 2003.
Abstract
Background: Aprepitant is a neurokinin1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated.
Methods: Study 1 was an open-label, randomized, incomplete-block, 3-period crossover study with 20 subjects. Treatment A consisted of a standard oral dexamethasone regimen for chemotherapy-induced nausea and vomiting (20 mg dexamethasone on day 1, 8 mg dexamethasone on days 2 to 5). Treatment B was used to examine the effects of oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 5) on the standard dexamethasone regimen. Treatment C was used to examine the effects of aprepitant on a modified dexamethasone regimen (12 mg dexamethasone on day 1, 4 mg dexamethasone on days 2 to 5). All subjects also received 32 mg ondansetron intravenously on day 1 only. Study 2 was a double-blind, randomized, placebo-controlled, 2-period crossover study with 10 subjects. Subjects in one group received a regimen consisting of 125 mg methylprednisolone intravenously on day 1 and 40 mg methylprednisolone orally on days 2 to 3. Subjects in the other group received oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 3) in addition to the methylprednisolone regimen.
Results: In study 1, the area under the concentration-time curve from 0 to 24 hours (AUC0-24) of oral dexamethasone on days 1 and 5 after the standard dexamethasone plus ondansetron regimen (treatment A) was increased 2.2-fold (P < .010) with coadministration of aprepitant (treatment B). Coadministration of aprepitant with the modified dexamethasone plus ondansetron regimen (treatment C) resulted in an AUC0-24 for dexamethasone similar to that observed after the standard dexamethasone plus ondansetron regimen (treatment A). In study 2, aprepitant increased the AUC0-24 of intravenous methylprednisolone 1.3-fold on day 1 (P < .010) and increased the AUC0-24 of oral methylprednisolone 2.5-fold on day 3 (P < .010).
Conclusions: Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma concentrations of the corticosteroids. These findings suggest that the dose of these corticosteroids should be adjusted when given with aprepitant.
