Miura Yuji, Imamura Chiyo K, Fukunaga Koya, Katsuyama Yoshihiko, Suyama Koichi, Okaneya Toshikazu, Mushiroda Taisei, Ando Yuichi, Takano Toshimi, Tanigawara Yusuke
Department of Medical Oncology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan.
BMC Cancer. 2014 Dec 16;14:964. doi: 10.1186/1471-2407-14-964.
Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects.
A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient.
The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.
舒尼替尼是一种多靶点受体酪氨酸激酶抑制剂，作用于血管内皮生长因子和血小板衍生生长因子的受体。舒尼替尼治疗的常见毒性包括高血压、手足综合征、呕吐和腹泻，所有类型中3级或4级不良事件的比例为1%至13%。据报道，舒尼替尼暴露增加与临床结局改善相关，但也会增加不良反应的风险。
一名73岁的日本转移性肾细胞癌女性患者，接受舒尼替尼治疗，剂量为每日50 mg一次，在治疗第11天出现高热。舒尼替尼治疗于第12天停药；然而，出现了严重血小板减少和转氨酶升高，并持续了一周多。此外，尽管立即停用舒尼替尼，但仍出现了因胸腔积液和肺水肿导致的严重缺氧。在停用舒尼替尼三天后的第14天，舒尼替尼及其主要活性代谢物N-去乙基舒尼替尼（SU12662）的血浆浓度极高（分别为131.9 ng/mL和28.4 ng/mL）。到第25天，所有毒性均已消退，CT扫描显示肿瘤明显缩小。对七个可能与舒尼替尼药代动力学相关的单核苷酸多态性进行了基因分型。患者ABCG2（ATP结合盒，G亚家族（白色），成员2）421C>A的基因型为变异等位基因纯合子（AA），据报道该基因型与舒尼替尼的高暴露有关。因此，我们推测ABCG2 421 AA基因型导致的舒尼替尼和SU12662血浆浓度极高可能给患者带来了严重毒性。
ABCG2 421C>A的次要等位基因频率在亚洲人中比在白种人中高约三倍。我们的报告表明，当亚洲患者（包括接受舒尼替尼治疗的日本人）发生严重且快速发作的药物不良反应时，应考虑药物遗传学因素。
