Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients

// Kazuyuki Numakura 1 , Nobuhiro Fujiyama 2 , Makoto Takahashi 1 , Ryoma Igarashi 1 , Hiroshi Tsuruta 1 , Atsushi Maeno 1 , Mingguo Huang 1 , Mitsuru Saito 1 , Shintaro Narita 1 , Takamitsu Inoue 1 , Shigeru Satoh 2 , Norihiko Tsuchiya 3 , Takenori Niioka 4 , Masatomo Miura 4 and Tomonori Habuchi 1 1 Department of Urology, Akita University Graduate School of Medicine, Akita, Japan 2 Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan 3 Department of Urology, Yamagata University, Faculty of Medicine, Yamagata, Japan 4 Division of Pharmaceutical Science, Akita University Hospital, Akita, Japan Correspondence to: Kazuyuki Numakura, email: numakura@doc.med.akita-u.ac.jp Keywords: renal cell carcinoma; sunitinib; N-desethyl-sunitinib; pharmacokinetics Received: December 01, 2017      Accepted: May 01, 2018      Published: May 18, 2018 ABSTRACT In this study, we examined the association between the pharmacokinetics (PK) level of sunitinib malate (SU) and its metabolite N-desethyl-sunitinib (DSU) in terms of adverse events (AEs) and clinical outcomes in patients with metastatic renal cell carcinoma (mRCC). The PK of sunitinib (SU and DSU) was examined in 26 patients (20 men and 6 women) with mRCC. The associations between SU/DSU C0 and AE occurrence, best response rate, time to treatment failure, progression-free survival (PFS), and overall survival (OS) were investigated. Occurrence of grade 1 or higher hand-foot syndrome and thrombocytopenia ( p = 0.002 and 0.024, respectively) was associated with a high concentration before morning intake (C0) level of SU. Low C0 levels of DSU were significantly associated with drug discontinuation due to disease progression ( p = 0.035). Patients with DSU C0 level higher than 15.0 ng/mL showed a tendency toward increased PFS (61 weeks vs 12 weeks, p = 0.004) and OS (36 months vs 8 months, p = 0.040). The C0 level of SU and SU + DSU were not associated with prognosis. The higher level of C0 of SU may predict developing AEs and DSU C0 >15.0 ng/mL may lead to better prognosis of patients treated with sunitinib. PK of sunitinib may be useful for determining adequate dosages and prevention of severe AEs. Further studies are required to establish the utility of the PK of sunitinib in patients with mRCC.