Elimination

Excretion is primarily via faeces (61%) with renal elimination of unchanged active substance and metabolites accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were the major compounds identified in plasma, urine and faeces, representing 91.5%, 86.4% and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and faeces, but generally were not found in plasma. Total oral clearance (CL/F) was 34-62 l/hr. Following oral administration in healthy volunteers, the elimination half-lives of sunitinib and its primary active desethyl metabolite are approximately 40 – 60 hours, and 80 – 110 hours, respectively.

Special Populations

Hepatic impairment: Sunitinib and its primary metabolite are mainly metabolized by the liver. Systemic exposures after a single dose of sunitinib were similar in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to subjects with normal hepatic function. SUTENT was not studied in subjects with severe (Child-Pugh class C) hepatic impairment.

Studies in cancer patients have excluded patients with ALT or AST >2.5 x ULN (Upper Limit of normal) or, if due to liver metastasis > 5.0 x ULN.

Renal impairment: Population pharmacokinetic analyses indicated that sunitinib apparent clearance (CL/F) was not affected by creatinine clearance within the range eva luated (42-347 ml/min).

Systemic exposures after a single dose of SUTENT were similar in subjects with severe renal impairment (CLcr<30 ml/min) compared to subjects with normal renal function (CLc>80 ml/min). Although sunitinib and its primary metabolite were not eliminated through hemodialysis in subjects with ESRD, the total systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared to subjects with normal renal function.

Weight, performance status: Population pharmacokinetic analyses of demographic data indicate that no starting dose adjustments are necessary for weight or Eastern Cooperative Oncology Group (ECOG) performance status.

Gender: Available data indicate that females could have about 30% lower apparent clearance (CL/F) of sunitinib than males: this difference, however, does not necessitate starting dose adjustments.
5.3 Preclinical safety data
 In rat and monkey repeated-dose toxicity studies up to 9-months duration, the primary target organ effects were identified in the gastrointestinal tract (emesis and diarrhoea in monkeys), adrenal gland (cortical congestion and/or haemorrhage in rats and monkeys, with necrosis followed by fibrosis in rats), haemolymphopoietic system (bone morrow hypocelularity, and lymphoid depletion of thymus, spleen, and lymph node), exocrine pancreas (acinar cell degranulation with single cell necrosis), salivary gland (acinar hypertrophy), bone joint (growth plate thickening), uterus (atrophy) and ovaries (decreased follicular development). All findings occurred at clinically relevant sunitinib plasma exposure levels. Additional effects, observed in other studies included QTc interval prolongation, LVEF reduction, pituitary hypertrophy, and testicular tubular atrophy, increased mesangial ce