Elsevier

Clinical Therapeutics

Volume 25, Issue 5, May 2003, Pages 1407-1419
Clinical Therapeutics

Original research
Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects

https://doi.org/10.1016/S0149-2918(03)80128-5Get rights and content

Abstract

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 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-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 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 (AUC0−∞), peak plasma concentration, and apparent terminal elimination half-life (t12) 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 AUC0−∞ 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 t12 (5.0 vs 4.5 hours, respectively). Coadministration of aprepitant 125 mg/80 mg did not alter the mean pharmacokinetic characteristics of oral granisetron (AUC0−∞, 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; t12, 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.

References (32)

  • Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC)
  • R.J. Gralla et al.

    Recommendations for the use of antiemetics: Evidence-based, clinical practice guidelines

    J Clin Oncol

    (1999)
  • F. Roila et al.

    Prevention of cisplatin-induced emesis: A double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone

    J Clin Oncol

    (1991)
  • P.J. Hesketh et al.

    A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis

    J Clin Oncol

    (1994)
  • P. Hesketh

    Management of cisplatin-induced delayed emesis

    Oncology

    (1996)
  • J. Latreille et al.

    Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy

    J Clin Oncol

    (1998)
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