Lutetium ¹⁷⁷Lu oxodotreotide

Lutetium (¹⁷⁷Lu) oxodotreotide has a high affinity for subtype 2 somatostatin receptors (sst2). It binds to malignant cells which overexpress sst2 receptors. Lutetium-177 (¹⁷⁷Lu) is a βemitting radionuclide with a maximum penetration range in tissue of 2.2 mm (mean penetration range of 0.67 mm), which is sufficient to kill targeted tumour cells with a limited effect on neighbouring normal cells.

Pharmacodynamic effects

At the concentration used (about 10 μg/mL in total, for both free and radiolabeled forms), the peptide oxodotreotide does not exert any clinically relevant pharmacodynamic effect.

Absorption

The medicinal product is administered intravenously and is immediately and completely bioavailable.

Organ uptake

At 4 hours after administration, the distribution pattern of lutetium (¹⁷⁷Lu) oxodotreotide shows a rapid uptake in kidneys, tumour lesions, liver and spleen, and in some patients in the pituitary gland and in the thyroid. The co-administration of amino acid solution decreases the kidney uptake, enhancing the elimination of radioactivity. Biodistribution studies show that lutetium (¹⁷⁷Lu) oxodotreotide is rapidly cleared from the blood.

An analysis performed with human plasma to determine the extent of plasma protein binding of non-radioactive compound (lutetium (¹⁷⁵Lu) oxodotreotide) showed that about 50% of the compound is bound to plasmatic proteins. Transchelation of lutetium from lutetium (¹⁷⁵Lu) oxodotreotide into serum proteins has not been observed.

Biotransformation

There is evidence, from the analysis of urine samples of 20 patients included in the NETTER-1 phase III Dosimetry, pharmacokinetic and ECG substudy, that lutetium (¹⁷⁷Lu) oxodotreotide is poorly metabolized and is excreted mainly as intact compound by renal route.

The high performance liquid chromatography (HPLC) analyses performed on urine samples collected up to 48 hours post infusion showed lutetium (¹⁷⁷Lu) oxodotreotide radiochemical purity close to 100% in most of the analysed samples (with lowest radiochemical purity value being greater than 92%), indicating that the compound is eliminated in urine mainly as intact compound.

This evidence confirms what has been previously observed in the Erasmus phase I/II study, in which HPLC analysis of a urine specimen collected 1 hour post administration of lutetium (¹⁷⁷Lu) oxodotreotide from one patient receiving 1.85 MBq of lutetium (¹⁷⁷Lu) oxodotreotide indicated that the main portion (91%) was excreted unchanged.

These finding are supported by in vitro metabolism data in human hepatocytes, in which no metabolic degradation of lutetium (175Lu) oxodotreotide was observed.

Elimination

Based on the data collected during the Erasmus phase I/II and NETTER-1 phase III studies, lutetium (¹⁷⁷Lu) oxodotreotide is primarily eliminated by renal excretion: about 60% of the medicinal product is eliminated in the urine within 24 hours, and about 65% within 48 hours following the administration.

Elderly

The pharmacokinetics profile in elderly patients (≥75 years) has not been established. No data are available.

Toxicological studies with rats have demonstrated that a single intravenous injection of up to 4,550 MBq/kg was well tolerated and no deaths were observed. When testing the cold compound (non-radioactive lutetium (¹⁷⁵Lu) oxodotreotide) as a single intravenous injection in rats and dogs at doses up to 20,000 µg/kg (rats) and 3,200 µg/kg (dogs), the compound was well tolerated in both species and no deaths were observed. Toxicity with four repeated administrations, once every 2 weeks, of 1,250 µg/kg of the cold compound in rats and 80 µg/kg in dogs was not observed. This medicinal product is not intended for regular or continuous administration. Mutagenicity studies und long-term carcinogenicity studies have not been carried out.

Non-clinical data on the cold compound (non-radioactive lutetium (¹⁷⁵Lu) oxodotreotide) reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity