Introduction

Therapeutic drug monitoring (TDM) has been recognized as a useful tool for optimizing the dosages of many drugs, even in molecular-targeted therapeutics. In this study, we examined the associations between the pharmacokinetics of sunitinib (SU) and its metabolite N-desethyl-sunitinib (DSU) and adverse events (AEs) and clinical outcomes in patients with metastatic renal cell carcinoma (mRCC).

Methods

The pharmacokinetics of SU and DSU were examined in 26 patients (20 male and 6 female patients) with mRCC. Plasma SU and DSU levels were measured using high-performance liquid chromatography, and a pharmacokinetic study was performed on day 7 in the first cycle of SU. The associations between SU/DSU pharmacokinetics and the occurrence of AEs, best response rate, progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS) were investigated.

Results

All patients were treated with 37.5 mg/day SU at the day of pharmacokinetics. The mean trough levels of SU and DSU were 76.7 and 16.8 ng/mL respectively. Occurrence of hand-foot syndrome and thrombocytopenia (P = 0.002 and 0.024 respectively by Mann-Whitney test) was associated with high trough levels of SU. Low trough levels of DSU were significantly associated with drug discontinuation due to disease progression and were associated with worse tumor response (P = 0.035 and 0.042 respectively by Mann-Whitney test, Figure 1). Patients with DSU trough levels of or higher than 15.0 ng/mL showed a tendency toward increased PFS, TTF, and OS than those with trough levels lower than 15.0 ng/mL (Figure 2). SU trough levels were not associated with prognosis.

Conclusions

TDM of SU and DSU in patients with mRCC may be useful to determine adequate dosages and prevent severe AEs. Further studies are required to establish the usefulness of TDM of SU and DSU for ensuring long-term clinical efficacy in patients with mRCC.

Funding

none