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Print version ISSN 1516-3180
Sao Paulo Med. J. vol.127 no.6 São Paulo Nov. 2009
LETTER TO THE EDITOR
O antagonista do receptor de neuroquinina-1 aprepitante diminui a eficácia da quimioterapia baseada em ciclofosfamida?
Carlos Eduardo PaivaI; Bianca Sakamoto Ribeiro PaivaII; Odair Carlito MichelinIII
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
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.
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. [ Links ]
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. [ Links ]
3. van Schaik RH. CYP450 pharmacogenetics for personalizing cancer therapy. Drug Resist Updat. 2008;11(3):77-98. [ Links ]
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. [ Links ]
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. [ Links ]
Address for correspondence:
Carlos Eduardo Paiva
Faculdade de Medicina de Botucatu
Universidade Estadual Paulista (Unesp)
Centro de Oncologia e Hemato-Oncologia
Rubião Júnior District, s/nº
Botucatu (SP) - Brasil - CEP 18618-970
Tel. (+55 14) 3814-3640
Fax. (+55 14) 3815-6040
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