Does neurokinin-1-receptor antagonist aprepitant diminish the efficacy of cyclophosphamide-based chemotherapy?

O antagonista do receptor de neuroquinina-1 aprepitante diminui a eficácia da quimioterapia baseada em ciclofosfamida?

LETTER TO THE EDITOR

Does neurokinin-1-receptor antagonist aprepitant diminish the efficacy of cyclophosphamide-based chemotherapy?

O antagonista do receptor de neuroquinina-1 aprepitante diminui a eficácia da quimioterapia baseada em ciclofosfamida?

Carlos Eduardo Paiva^I; Bianca Sakamoto Ribeiro Paiva^II; Odair Carlito Michelin^III

^IMD, MSc. PhD student and clinical oncologist, Oncological and Hemato-Oncological Center, Universidade Estadual Paulista (Unesp), Botucatu, São Paulo, Brazil

^IIRN, MSc. PhD student and assistant nursing professor, Department of Nursing, Botucatu Medical School, Universidade Estadual Paulista (Unesp), Botucatu, São Paulo, Brazil

^IIIMD, PhD. Associate professor, Department of Clinics, Botucatu Medical School, Universidade Estadual Paulista (Unesp), Botucatu, São Paulo, Brazil

^{Address for correspondence}

Neurokinin-1-receptor antagonist aprepitant has been approved for clinical use based on two prospective phase III trials conducted with cisplatin-based highly emetogenic chemotherapy.¹ It was developed for use in combination with a 5-HT3-receptor antagonist and corticosteroid in order to prevent both acute and delayed chemotherapy-induced nausea and vomiting (CINV). Warr et al.² have suggested that aprepitant could be a useful antiemetic for prevention of CINV associated with moderately emetogenic chemotherapy, such as the adriamycin/cyclophosphamide (AC) regimen used for breast cancer treatment.

Aprepitant is metabolized primarily via cytochrome P-450 (CYP) 3A4-mediated oxidation, with minor metabolism by other cytochromes.³ The alkylating agent cyclophosphamide is an inactive prodrug that requires activation to form its active metabolite 4-hydroxycyclophosphamide (4-HOCP), with major participation by CYP2A6, CYP2B6 and CYP3A4.³ de Jonge et al.⁴ have shown that aprepitant inhibits cyclophosphamide metabolism, thus resulting in decreased formation of 4-HOCP.

It was with great interest that we read the recent paper by Yeo et al.⁵ concerning aprepitant-based CINV prophylaxis in moderately emetogenic chemotherapy. They studied a homogeneous group of Chinese breast cancer patients who underwent adjuvant AC chemotherapy (i.e. doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m²). They unexpectedly found lower incidences of neutropenia of grade > 3, and delay in the subsequent chemotherapy cycle. These important results led us to consider the possibility that aprepitant and cyclophosphamide drug interactions could decrease 4-HOCP formation and affect treatment efficacy.

By considering cytochrome P450 genetic polymorphisms among different breast cancer populations, we think that the clinical relevance of the aforementioned drug interaction should be urgently addressed in new studies and in different ethnic groups.

Date of first submission: February 27, 2009

Last received: November 25, 2009

Accepted: November 30, 2009

Sources of funding: Not declared

Conflict of interest: Not declared

• 1. Warr DG, Grunberg SM, Gralla RJ, et al. The oral NK(1) antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: Pooled data from 2 randomised, double-blind, placebo controlled trials. Eur J Cancer. 2005;41(9):1278-85.
• 2. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol. 2005;23(12):2822-30.
• 3. van Schaik RH. CYP450 pharmacogenetics for personalizing cancer therapy. Drug Resist Updat. 2008;11(3):77-98.
• 4. de Jonge ME, Huitema AD, Holtkamp MJ, van Dam SM, Beijnen JH, Rodenhuis S. Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. Cancer Chemother Pharmacol. 2005;56(4):370-8.
• 5. Yeo W, Mo FK, Suen JJ, et al. A randomized study of aprepitant, ondansetron and dexamethasone for chemotherapy-induced nausea and vomiting in Chinese breast cancer patients receiving moderately emetogenic chemotherapy. Breast Cancer Res Treat. 2009;113(3):529-35.

Publication Dates

• Publication in this collection
  21 May 2010
• Date of issue
  Nov 2009