Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone.
BACKGROUND
Aprepitant is a neurokinin(1) receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine(3) 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 (AUC(0-24)) 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.
McCrea
Jacqueline B
JB
Merck Research Laboratories, Bluebell, PA 19422, USA.
Majumdar
Anup K
AK
Goldberg
Michael R
MR
Iwamoto
Marian
M
Gargano
Cynthia
C
Panebianco
Deborah L
DL
Hesney
Michael
M
Lines
Christopher R
CR
Petty
Kevin J
KJ
Deutsch
Paul J
PJ
Murphy
M Gail
MG
Gottesdiener
Keith M
KM
Goldwater
D Ronald
DR
Blum
Robert A
RA
D000328:Adult; D000704:Analysis of Variance; D000077608:Aprepitant; D019540:Area Under Curve; D016001:Confidence Intervals; D018592:Cross-Over Studies; D003907:Dexamethasone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000502:physiology
D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D003907:Dexamethasone; D008775:Methylprednisolone