Sunitinib-induced severe toxicities in a Japanese patient with the ABCG2 421 AA genotype

Abstract

BackgroundSunitinib 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.Case presentationA 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.ConclusionThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-964) contains supplementary material, which is available to authorized users.

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…It was reported that this SNP was associated with an increase in systemic exposure to sunitinib, possibly causing thrombocytopenia and hypertension [23]. Miura et al [24] followed with a case report in 2014 describing a patient with mRCC who developed severe grade 3 and 4 adverse events on sunitinib, namely fever, thrombocytopenia, transaminase elevation, hypoxia, and pulmonary edema. Again, the AA genotype of rs2231142 in ABCG2 was suggested to explain these toxicities in Asians.…”

PharmGKB summary

“…A study in people of Japanese descent reported a 1.9 - 3.5 times greater AUC of sulfasalazine in patients with the c.421C>A variant, but this finding was not replicated in a study of people of Chinese descent [83]. Other studies found that patients of Japanese descent with the c.421C>A variant who were being treated with sunitinib for advanced renal cell carcinoma were more likely to develop grade 3 or grade 4 thrombocytopenia [81,84,85], and that the variant was significantly associated with increased sunitinib exposure [86]. Furthermore, patients homozygous for the reference allele may have lower plasma concentrations of atorvastatin, simvastatin, and fluvastatin [1,87,88] and may respond more poorly to FOLFOX/XELOX therapy [89] compared to patients homozygous for the A allele.…”

Continuous remission of renal cell carcinoma with tumour thrombus after severe adverse events following short-term treatment with sunitinib

“…Miura et al described a patient with metastatic RCC who exhibited grade 4 thrombocytopaenia and a 30% reduction in lesions after sunitinib treatment for 10 days 5. In that case, the blood concentration of sunitinib was much higher than usual.…”