Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects.
BACKGROUND
The neurokinin-1-receptor antagonist aprepitant, when given in combination with a corticosteroid and a 5-hydroxytryptamine type 3 (5-HT(3))-receptor antagonist, has been shown to be effective for the prevention of acute and delated chemotherapy-induced nausea and vomiting (CINV).


OBJECTIVE
Two studies were conducted to determine whether concomitant administration of aprepitant altered the pharmacokinetic profiles of ondansetron and granisetron, two 5-HT(3)-receptor antagonists commonly used as antiemetic therapy for CINV.


METHODS
The 2 studies were randomized, open-label, crossover trials conducted in healthy subjects aged between 18 and 46 years. Study 1 involved the following 2 treatment regimens: aprepitant 375 mg PO, dexamethasone 20 mg PO, and ondansetron 32 mg IV on day 1, followed by aprepitant 250 mg PO and dexamethasone 8 mg PO on days 2 through 5; and dexamethasone 20 mg PO and ondansetron 32 mg IV on day 1, followed by dexamethasone 8 mg PO on days 2 through 5. Study 2 involved the following 2 treatment regimens: aprepitant 125 mg PO with granisetron 2 mg PO on day 1, followed by aprepitant 80 mg PO on days 2 and 3; and granisetron 2 mg PO on day 1 only. Individual plasma samples were used to estimate area under the plasma concentration-time curve from time zero to infinity (AUC(0- infinity )), peak plasma concentration, and apparent terminal elimination half-life (t(12)) of both ondansetron and granisetron.


RESULTS
Study 1 included 19 subjects (10 women, 9 men), and study 2 included 18 subjects (11 men, 7 women). Coadministration of aprepitant 375 mg produced a small but statistically significant increase in the AUC(0- infinity ) for intravenous ondansetron (from 1268.3 to 1456.5 ng.h/mL; P = 0.019), with no significant effect on peak concentration at the end of the infusion (360.8 ng/mL with aprepitant vs 408.4 ng/mL without) or t(12) (5.0 vs 4.5 hours, respectively). Coadministration of aprepitant 125 mg/80 mg did not alter the mean pharmacokinetic characteristics of oral granisetron (AUC(0- infinity ), 101.4 ng.h/mL with aprepitant vs 92.2 ng.h/mL without; maximum plasma concentration, 9.0 ng/mL with and without aprepitant; time to maximum plasma concentration, both 3.0 hours; t(12), 6.5 vs 6.9 hours, respectively).


CONCLUSIONS
Concomitant administration of aprepitant had no clinically significant effect on the mean pharmacokinetic characteristics of either ondansetron or granisetron in these healthy subjects.
Blum
Robert A
RA
Buffalo Clinical Research Center, Buffalo, New York, USA
Majumdar
Anup
A
McCrea
Jacqueline
J
Busillo
John
J
Orlowski
Laura H
LH
Panebianco
Deborah
D
Hesney
Michael
M
Petty
Kevin J
KJ
Goldberg
Michael R
MR
Murphy
M Gail
MG
Gottesdiener
Kevin M
KM
Hustad
Carolyn M
CM
Lates
Christian
C
Kraft
Walter K
WK
Van Buren
Sandi
S
Waldman
Scott A
SA
Greenberg
Howard E
HE
D000328:Adult; D000932:Antiemetics / Q000378:metabolism / Q000493:pharmacokinetics*; D000077608:Aprepitant; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D017829:Granisetron / Q000378:metabolism / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology*; D017294:Ondansetron / Q000378:metabolism / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic
D000932:Antiemetics; D000077608:Aprepitant; D017829:Granisetron; D009025:Morpholines; D017294:Ondansetron