Introduction

Sunitinib (SU) is an oral multi-targeted tyrosine kinase inhibitor (TKI) for renal cell carcinoma (RCC). Because of severe adverse events (AEs) associated with its use, patients have to either reduce the dose or cease taking SU. Single-nucleotide polymorphisms (SNPs) from the ABCB1, ABCG2, CYP3A4, and CYP3A5 genes were reported to have an effect on individual pharmacokinetic variation in oral bioavailability of other TKIs. The aim of this study was to determine whether there exists an association between these SNPs with individual variation in sunitinib plasma concentration.

Methods

From April 2006 to July 2015, we administrated SU to 80 metastatic RCC (mRCC) patients at Akita University. Of these patients, the pharmacokinetics of SU and its metabolite, N-desethyl sunitinib (DSU), were examined in 25 cases (19 males and 6 females). Plasma SU and DSU levels were measured using high-performance liquid chromatography, and a pharmacokinetic study was performed on day 7 of the first cycle. We tested for association between SU and DSU pharmacokinetics with SNP genotype and allele frequencies.

Results

All patients were treated with 37.5 mg/day of SU on the day of pharmacokinetic assessment, and had mean trough levels of 76.7 ng/mL and 16.8 ng/mL for SU and DSU, respectively. The ABCB1 1236 TT genotype was associated with high SU trough levels compared to that found in patients with a #T or ## genotype (95.9 ng/mL versus 61.6 ng/mL, respectively; P = 0.030). In addition, the ABCB1 2677 G allele was associated with high DSU trough levels compared to that seen with the 2677 # allele (12.7 ng/mL versus 18.8 ng/mL, respectively; P = 0.047) (Table 1).

Conclusions

Our study found that the ABCB1 1236 TT genotype and the 2677 G allele were associated with increased trough levels of SU and DSU, respectively. Based on our findings, the pharmacokinetics of SU and DSU may be informative indicators to determine effective dosage and prevent manifestation of severe AEs in patients with mRCC. Further evaluation of ABCB1 genotypes and sunitinib dosage is warranted.

Funding

none