Association of ABCB1, 5-HT3B Receptor and CYP2D6 Genetic Polymorphisms with Ondansetron and Metoclopramide Antiemetic Response in Indonesian Cancer Patients Treated with Highly Emetogenic Chemotherapy
1. Dyah A. Perwitasari1,2,3,
2. Judith A.M. Wessels2,
3. Robert J.H.M. van der Straaten2,
4. Renee F. Baak-Pablo2,
5. Mustofa Mustofa3,
6. Mohammad Hakimi4,
7. Johann W.R. Nortier5,
8. Hans Gelderblom5 and
9. Henk-Jan Guchelaar2,*
+ Author Affiliations
1Department of Pharmacy, Ahmad Dahlan University, Yogyakarta, Indonesia
2Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
3Department of Pharmacology and Therapy, Universitas Gadjah Mada
4Department of Obstetric and Gynaecology, Universitas Gadjah Mada, Yogyakarta, Indonesia
5Department of Clinical Oncology, LUMC, Leiden, The Netherlands
1. ↵*For reprints and all correspondence: H-J. Guchelaar, Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, PO Box 9600, NL 2300 RC Leiden, The Netherlands. E-mail: email@example.com
* Received May 10, 2011.
* Accepted July 16, 2011.
Objective Suboptimal treatment of chemotherapy-induced nausea and vomiting and unsatisfactory response to antiemetic drugs cause impairment of cancer patient’s daily functioning. This study was aimed to investigate the association of selected germline polymorphisms with ondansetron and metoclopramide response in Indonesian cancer patients treated with highly emetogenic chemotherapy.
Methods We enrolled 202 chemotherapy naïve patients treated with cisplatin at a dosage of ≥50 mg/m2 as monotherapy or as combined chemotherapy. Ondansetron 8 mg and dexamethasone 8 mg intravenously were the standard antiemetic therapy for prevention of acute chemotherapy-induced nausea and vomiting. Metoclopramide 10 mg orally, three times per day as fixed prescription, was given until 5 days after chemotherapy to prevent delayed chemotherapy-induced nausea and vomiting. Primary and secondary outcomes were the occurrence of chemotherapy-induced nausea and vomiting in the acute and delayed phase. The following single-nucleotide polymorphisms were determined in ABCB1: rs1045642, rs2032582 and rs1128503; in 5-HT3B-R: rs45460698, rs4938058 and rs7943062; and in CYP2D6: rs16947 (CYP2D6*2), rs3892097 (CYP2D6*4) and rs1065852 (CYP2D6*10) using Taqman assays.
Results During the acute phase, 21.8 and 30.2% patients experienced Grade 3 and 4 nausea and vomiting, respectively, whereas 38.6% patients experienced nausea and/or vomiting in the delayed phase. Carriers of the CTG haplotype of the ABCB1 gene experienced Grade 3 and 4 chemotherapy-induced nausea and vomiting more often than other haplotypes in the delayed phase (P< 0.05). No associations were found with the 5-HT3B receptor haplotypes and CYP2D6-predicted phenotypes.
Conclusions Our study shows that in Indonesian cancer patients treated with highly cytostatic emetogenic, carriership of the CTG haplotype of the ABCB1 gene is related to an increased risk of delayed chemotherapy-induced nausea and vomiting.