Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients

Kim, Hye Ryun; Park, Hyung Soon; Kwon, Woo Sun; Lee, Ji Hyun; Lim, Sun Min; Kim, Hyo Song; Shin, Sang Joon; Ahn, Joong Bae; Rha, Sun Young

doi:10.1007/s00280-013-2258-y

Cited by 60 publications

(51 citation statements)

References 33 publications

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“…The association of sunitinib-induced toxicities with pharmacogenetic determinants was studied by Kim et al in 65 Korean mRCC patients [49]. Compared to C-allele carriers, patients with the AA variant genotype of the drug transporter ABCG2 rs2231142 had an increased risk for grade 3 or 4 thrombocytopenia, neutropenia and hand-foot syndrome [49]. As to the relation of this SNP with pharmacokinetic parameters, Mizuno et al clarified the effect of the ABCG2 rs2231142 genotype in 19 Japanese RCC patients [50,51].…”

Section: Discussionmentioning

confidence: 99%

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

et al. 2016

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Background: An increasing number of studies have reported ethnic differences in sunitinib outcome in metastatic renal cell carcinoma (mRCC) patients. However, a comprehensive analysis is still lacking. Therefore, we systematically collected available published data and performed a meta-analysis to compare sunitinib efficacy and toxicity in Asian and Caucasian mRCC patients. Methods: Data were extracted from published results from clinical trials, expanded access program and real-world clinical practice. Progression-free survival (or time to tumor progression), overall survival, objective response rate and adverse events were used as endpoints to evaluate the differences of sunitinib outcome between the two ethnicities. For adverse events, we focused the following clinically relevant side effects: diarrhea, fatigue, mucositis/stomatitis, hand-foot syndrome, hypertension, leukopenia, neutropenia and thrombocytopenia. Results: A total of 33 publications including 9977 patients were available for meta-analysis. The efficacy of sunitinib in Asian patients was similar to that in Caucasian patients. However, Asian patients showed a higher incidence of all grades toxicity of hand-foot syndrome, > grade 2 fatigue, > grade 2 hand-foot syndrome and > grade 2 thrombocytopenia. Conclusion: Ethnic differences in adverse events of sunitinib in mRCC patients existed and dose adjustment in Asian patients may be considered.

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Section: Discussionmentioning

confidence: 99%

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

et al. 2016

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“…Sunitinib-induced toxicities in relation to pharmacogenetic determinants were studied by Kim et al [27] in a number of 65 Korean mRCC patients. Compared to C-allele carriers, the AA genotype of rs2231142 in ABCG2 had an increased risk for grade 3 or 4 thrombocytopenia, neutropenia, and HFS [27].…”

Section: Pharmacogenetics To Predict Sunitinib Toxicitymentioning

confidence: 99%

“…Compared to C-allele carriers, the AA genotype of rs2231142 in ABCG2 had an increased risk for grade 3 or 4 thrombocytopenia, neutropenia, and HFS [27]. In addition, a case report of Takayoshi et al [28] reported a 65-year-old woman with mRCC who showed severe toxicities and was found to have the TTT haplotype on ABCB1 (rs1045642, rs1128503, rs2032582).…”

Section: Pharmacogenetics To Predict Sunitinib Toxicitymentioning

confidence: 99%

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

Diekstra

Swen

Gelderblom

et al. 2016

Expert Review of Molecular Diagnostics

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“…9,10) This genetic polymorphism has been associated with sunitinib-induced toxicities. 11) In addition, the allele frequency of ABCG2 421C>A was found to be higher in Asians than in non-Asians, such as Caucasians and African-Americans. 12) These findings suggested that the ABCG2 polymorphism may represent one of the reasons for the ethnic differences reported in sunitinib PK and toxicity.…”

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confidence: 99%

Pharmacokinetic–Pharmacodynamic Analysis of Sunitinib-Induced Thrombocytopenia in Japanese Patients with Renal Cell Carcinoma

Nagata

Ishiwata

Takahashi

et al. 2015

Biological & Pharmaceutical Bulletin

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The aim of the present study was to clarify the therapeutic range and adequate dose of sunitinib in Japanese renal cell carcinoma patients by means of a pharmacokinetic-pharmacodynamic analysis of sunitinibinduced thrombocytopenia. Six patients with renal cell carcinoma were enrolled in this study. After starting the sunitinib treatment, between three and seven blood samples were obtained from each patient just before the administration of sunitinib. Serum concentrations of sunitinib and its active metabolite N-desethylsunitinib were fit to the 1-compartment model with first-order absorption. Changes in platelet counts were fit to the pharmacokinetic-pharmacodynamic model, in which the proliferation of platelet progenitor cells was assumed to be linearly inhibited by sunitinib and its metabolite. All patients using 50 mg as an initial dose of sunitinib developed grade 2 or 3 thrombocytopenia. The pharmacokinetic-pharmacodynamic model created successfully described the time course of sunitinib-induced thrombocytopenia and could predict changes in platelet counts after alterations to the dosage of sunitinib administered. The simulation results indicated that the total trough level of sunitinib to avoid severe thrombocytopenia should be <100 ng/mL, and also that the initial daily dose of sunitinib could be reduced to 37.5 mg or 25 mg in most Japanese patients. In addition to the pharmacokinetic-guided dosage adjustment, the careful monitoring of platelet counts is required for the safe use of sunitinib.

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Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients

Abstract: Among 12 genetic polymorphisms, polymorphism in the ABCG2 421C>A gene may be mostly associated with the risk of sunitinib-related toxicity in mRCC patients. Considering the high frequency of 421C>A SNP in Asian, this may be related to differential toxicities among ethnic groups.

Cited by 60 publications

References 33 publications

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

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

Pharmacokinetic–Pharmacodynamic Analysis of Sunitinib-Induced Thrombocytopenia in Japanese Patients with Renal Cell Carcinoma

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