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-HT3)-receptor antagonist, has been shown to be effective for the prevention of acute and delayed 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-HT3-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 I 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(1/2)) 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(1/2) (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(1/2), 6.5 vs 6.9 hours, respectively). Conclusion: Concomitant administration of aprepitant had no clinically significant effect on the mean pharmacokinetic characteristics of either ondansetron or granisetron in these healthy subjects. Copyright (C) 2003 Excerpta Medica, Inc.