The patient was a 66-year-old man diagnosed with RCC following macroscopic hematuria in August 2007. He underwent radical nephrectomy for clear-cell carcinoma (stage pT1a cN0 cM0, R0, G2>G3) of the right kidney in September 2007. He started chronic dialysis in September 2007. In August 2008, he developed lung metastases and underwent partial lung resection. In March 2010, he developed further lung metastases. In April 2010, he was treated with interferon-α at 3 million units 3 times weekly, which was discontinued in February 2011 because of severe general malaise. In May 2011, lung metastases were increased, indicating progression. In August 2011, he was treated with sunitinib at 25 mg daily for 4 weeks of a 6-week cycle. The Eastern Cooperative Oncology Group performance status was 0. He was classified as being at intermediate risk according to the Memorial Sloan-Kettering Cancer Center risk criteria. His past medical history included hypertension. He had not been administered any medication that inhibited CYP3A4.
Hemodialysis was performed for 4 h, 3 times weekly. An APS-18SA polysulfone dialyzer (surface area 1.8 m2) with internal shunt was used. The dialysate flow rate was constant at 500 ml/min and the blood flow rate was 230 ml/min.
We evaluated the PK of sunitinib and SU12662 during the course of the first cycle on day 17 (on hemodialysis) and on day 18 (off hemodialysis). After obtaining written informed consent from the patient, blood samples were collected just before administration (0) and then 2, 6, 12 and 24 h after administration. The 4-hour dialysis session started 2 h after administration. Blood samples were collected in sterilized vacuum tubes for serum separation. The samples were centrifuged (1,700 g at 4°C for 10 min), and the harvested serum was stored at −20°C. Acetonitrile (1 ml) was added to 500 μl of serum and vortexed thoroughly. After centrifugation at 11,000 rpm for 10 min at room temperature, the supernatant was transferred into propylene tubes and evaporated at 65°C under a nitrogen stream. Sunitinib and SU12662 were measured by high-performance liquid chromatography. The residue was dissolved with 400 μl of phosphate buffer (pH 2.5) and injected into the high-performance liquid chromatography system. Chromatographic separation was carried out under the following conditions. Shim-pack XR-ODS® (75 × 3.0 mm i.d.) column was used. The mobile phase was composed of 72% phosphate buffer (pH 2.5) and 28% acetonitrile. The flow rate was 1.0 ml/min. UV detection was performed at 423 nm. The injection volume was 40 μl at 40°C. The area under the concentration-time curve (AUC) was computed according to the trapezoidal rule. There were little differences in the AUC0–24 h of sunitinib and SU12662 on day 17 and day 18 during the course of the first cycle (fig. and table ). In addition, we measured serum trough concentrations of sunitinib and SU12662 at a steady state of each cycle of treatment. Serum total sunitinib concentrations (sunitinib and SU12662) were 50.7 ng/ml on day 28 of the first cycle, 51.2 ng/ml on day 19 of the second cycle and 50.2 ng/ml on day 19 of the third cycle.
Plasma concentrations of sunitinib and SU12662 on day 17 (on hemodialysis) and day 18 (off hemodialysis). Arrows indicate administration of 25 mg of sunitinib. The 4-hour dialysis session started 2 h after administration on day 17. HD = Hemodialysis.
PK parameters and serum concentrations of sunitinib, SU12662 and total drug (sunitinib + SU12662) on day 17 (on HD) and on day 18 (off HD)
Furthermore, in this patient, we assessed genetic polymorphisms related to the PK of sunitinib. Genotyping of single-nucleotide polymorphisms (SNPs) was performed using Custom TaqMan SNP genotyping assays. A previous study reported that ABCG2
421C>A was associated with increased sunitinib exposure [7
]. The patient's genotype was wild type for ABCG2
Following two cycles of sunitinib, computed tomography scan showed a partial response of the lung metastasis with 39% size reduction from that at baseline according to the Response Evaluation Criteria in Solid Tumors (fig. ). During the first cycle, the patient developed grade 2 thrombocytopenia and leukocytopenia and grade 1 hand-foot syndrome according to Common Toxicity Criteria for Adverse Effect v4.0. After four cycles of treatment, he developed grade 3 fatigue and thus sunitinib treatment was discontinued.
Tumor responses of lung metastases. Computed tomography scan images of the patient's lungs before administration of sunitinib (a) and 2 cycles after initiation of sunitinib (b). Arrows point to the metastatic lung lesion.