The European Medicines Agency has deferred the obligation to submit the results of the studies with SUTENT in one or more subsets of the paediatric population in gastrointestinal stromal tumours (GIST) (see section 4.2 for information on the paediatric use).

The European Medicines Agency has waived the obligation to submit the results of studies with SUTENT in all subsets of the paediatric population for treatment of kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) (see section 4.2 for information on paediatric use).

The European Medicines Agency has waived the obligation to submit the results of the studies with SUTENT in all subsets of the paediatric population for treatment of gastroenteropancreatic neuroendocrine tumours (excluding neuroblastoma, neuroganglioblastoma, phaeochromocytoma) (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties

 The pharmacokinetics of sunitinib has been eva luated in 135 healthy volunteers and 266 patients with solid tumours. The pharmacokinetics were similar in all solid tumours populations tested and in healthy volunteers.

In the dosing ranges of 25 to 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionally with dose. With repeated daily administration, sunitinib accumulates 3- to 4-fold and its primary active metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By day 14, combined plasma concentrations of sunitinib and is active metabolite are 62.9 - 101 ng/ml which are target concentrations predicted from preclinical data to inhibit receptor phosphorylation in vitro and result in tumour stasis/growth reduction in vivo. The primary active metabolite comprises 23 to 37% of the total exposure. No significant changes in the pharmacokinetics of sunitinib or the primary, active metabolite are observed with repeated daily administration or with repeated cycles in the dosing schedules tested.
Absorption

After oral administration of sunitinib, maximum concentrations (Cmax) are generally observed from 6 to 12 hours (Tmax) post-administration.

Food has no effect on the bioavailability of sunitinib.

Distribution

In vitro binding of sunitinib and its primary active metabolite to human plasma protein was 95% and 90%, respectively, with no apparent concentration dependence. The apparent volume of distribution (Vd) for sunitinib was large, 2230 l, indicating distribution into the tissues.

Metabolic interactions

The calculated in vitro Ki values for all cytochrome (CYP) isoforms tested (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 and CYP4A9/11) indicated that sunitinib and its primary active metabolite are unlikely to induce metabolism, to any clinically relevant extent, of other active substances that may be metabolized by these enzymes.

Biotransformation

Sunitinib is metabolized primarily by CYP3A4, the cytochrome P450 isoform, which produces its primary active metabolite, desethyl sunitinib, which is then further metabolized by the sam