Gaeun Kang1, Ka-Rham Kim2, Hyun-Jeong Shim2, Jun-Eul Hwang2, Woo-Kyun Bae2, Ik-Joo Chung2, Hee-Nam Kim3, Jongtae Lee4, Kyungmee Choi4,5, Hee-Young Shin1,6, Jong-Keun Kim1,7, Seong-Wook Jeong1,8, Sang-Hee Cho2. 1. Division of Clinical Pharmacology, Chonnam National University Hospital, Gwangju, Korea. 2. Department of Hematology-Oncolgy, Chonnam National University Medical School, Gwangju, Korea. 3. Department of Preventive Medicine, Chonnam National University, Gwangju, Korea. 4. PIPET (Pharmacometrics Institute for Practical Education and Training), Seoul, Korea. 5. Division of Mathematics, College of Science and Technology, Hongik University at Sejong, Jochiwon, Chungnam, Korea. 6. Department of Biomedical Science, Chonnam National University Medical School, Gwangju, Korea. 7. Department of Pharmacology, Chonnam National University Medical School, Gwangju, Korea. 8. Department of Anethesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Korea.
Abstract
AIM: Despite appropriate use of antiemetics including 5-hydroxytryptamine type 3 (5-HT3 ) receptor antagonists, chemotherapy-induced nausea and vomiting (CINV) is still an unsolved problem in patients with anticancer drugs. We examined whether the variants of ABCB1, CYP2D6 and HTR3B affect efficacy of ramosetron, a selective 5-HT3 receptor antagonist in a dose escalation clinical trial. METHODS: We conducted a clinical trial on patients who underwent FOLFOX combination chemotherapy. The participants were randomized into three groups of ramosetron: 0.3 mg (standard dose), 0.45 mg and 0.6 mg. Rhodes index of nausea, vomiting and retching were measured at 1, 6 h, day 1, day 2 and day 7 after the administration of ramosetron as a clinical parameter of CINV and polymorphism was analyzed from genomic DNA. RESULTS: There was a dose-dependent decrease in the nausea and vomiting scores at day 1 and day 2, not statistically significant. The Rhodes index of nausea, vomiting and retching score at day 1 in participants with HTR3B-100_-102delAAG deletion variants was significantly higher than wild type participants, regardless of dosages. However, the polymorphisms including ABCB1, CYP2D6 and other HTR3B genes did not affect response to ramosetron after chemotherapy. CONCLUSION: These results suggest that the -AAG deletion variant of the 5-HT3B receptor gene may contribute to variability in response to antiemetic therapy for CINV regardless of dose escalation. These results suggest that carrying a -100_-102delAAG variant of 5-HT3 gene should be supported by alternate or additive antiemetics in addition to 5-HT3 antagonists to control acute emesis.
RCT Entities:
AIM: Despite appropriate use of antiemetics including 5-hydroxytryptamine type 3 (5-HT3 ) receptor antagonists, chemotherapy-induced nausea and vomiting (CINV) is still an unsolved problem in patients with anticancer drugs. We examined whether the variants of ABCB1, CYP2D6 and HTR3B affect efficacy of ramosetron, a selective 5-HT3 receptor antagonist in a dose escalation clinical trial. METHODS: We conducted a clinical trial on patients who underwent FOLFOX combination chemotherapy. The participants were randomized into three groups of ramosetron: 0.3 mg (standard dose), 0.45 mg and 0.6 mg. Rhodes index of nausea, vomiting and retching were measured at 1, 6 h, day 1, day 2 and day 7 after the administration of ramosetron as a clinical parameter of CINV and polymorphism was analyzed from genomic DNA. RESULTS: There was a dose-dependent decrease in the nausea and vomiting scores at day 1 and day 2, not statistically significant. The Rhodes index of nausea, vomiting and retching score at day 1 in participants with HTR3B-100_-102delAAG deletion variants was significantly higher than wild type participants, regardless of dosages. However, the polymorphisms including ABCB1, CYP2D6 and other HTR3B genes did not affect response to ramosetron after chemotherapy. CONCLUSION: These results suggest that the -AAG deletion variant of the 5-HT3B receptor gene may contribute to variability in response to antiemetic therapy for CINV regardless of dose escalation. These results suggest that carrying a -100_-102delAAG variant of 5-HT3 gene should be supported by alternate or additive antiemetics in addition to 5-HT3 antagonists to control acute emesis.
Authors: Sylvia L Crowder; Aasha I Hoogland; Taylor L Welniak; Elizabeth A LaFranchise; Kristen M Carpenter; Daneng Li; Daniel M Rotroff; Arshiya Mariam; Christine M Pierce; Stacy M Fischer; Anita Y Kinney; Thi Dong-Binh Tran; Farzaneh Rastegari; Donna L Berry; Martine Extermann; Richard D Kim; Danielle B Tometich; Jane C Figueiredo; Jameel Muzaffar; Shahla Bari; Kea Turner; George M Weinstock; Heather S L Jim Journal: Cancer Date: 2021-10-13 Impact factor: 6.860