Lanreotide

Lanreotide is an octapeptide analogue of natural somatostatin. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions. Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5, and a reduced binding affinity for human SSTR 1, 3 and 4. Activity at human SSTR 2 and 5 is the primary mechanism considered to be responsible for GH inhibition. Lanreotide is more active than natural somatostatin and shows a longer duration of action.

Lanreotide, like somatostatin, exhibits a general exocrine anti-secretory action. It inhibits the basal secretion of motilin, gastric inhibitory peptide and pancreatic polypeptide, but has no significant effect on fasting secretin or gastrin secretion. Additionally, it decreases the levels of plasma chromogranin A and urinary 5-HIAA (5 Hydroxyindolacetic acid) in patients with GEP-NETs and elevated levels of these tumour markers.

Lanreotide markedly inhibits meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow.

Lanreotide significantly reduces prostaglandin E1-stimulated jejunal secretion of water, sodium, potassium and chloride.

Lanreotide reduces prolactin levels in patients with acromegaly patients treated long term.

Intrinsic pharmacokinetic parameters of lanreotide after intravenous administration in healthy volunteers indicated limited extravascular distribution, with a steady-state volume of distribution of 16.1 L. Total clearance was 23.7 L/h, terminal half-life was 1.14 hours and mean residence time was 0.68 hours.

In studies evaluating excretion, less than 5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in faeces indicating some biliary excretion.

After deep subcutaneous administration of lanreotide 60, 90 and 120 mg to healthy volunteers, lanreotide concentrations increase to achieve average maximum serum concentrations of 4.25, 8.39 and 6.79 ng/ml, respectively. These values of C_max are achieved during the first day after the administration at 8, 12 and 7 hours (median values). From the peak serum levels of lanreotide, concentrations decrease slowly following first-order kinetics with a terminal elimination half-life of 23.3, 27.4 and 30.1 days respectively. 4 weeks after the administration mean lanreotide serum levels were 0.9, 1.11 and 1.69 ng/ml respectively. Absolute bioavailability was 73.4, 69.0 and 78.4%, respectively.

After deep subcutaneous administration of lanreotide 60, 90 and 120 mg to patients with acromegaly, lanreotide concentrations increase to achieve average maximum serum concentrations of 1.6, 3.5 and 3.1 ng/ml, respectively. These values of C_max are achieved during the first day after the administration at 6, 6 and 24 hours. From the peak serum levels of lanreotide, concentrations decrease slowly following first-order kinetics and 4 weeks after the administration mean lanreotide serum levels were 0.7, 1.0 and 1.4 ng/ml, respectively.

Steady state serum levels of lanreotide were reached, on average, after 4 injections every 4 weeks. After repeated dose administration every 4 weeks the average values of C_max at steady state were 3.8, 5.7 and 7.7 ng/ml for 60, 90 and 120 mg respectively, the average C_min values obtained being 1.8, 2.5 and 3.8 ng/ml. The peak trough fluctuation index was moderate ranging from 81 to 108%.

Linear pharmacokinetic release profiles were observed after deep subcutaneous administration of lanreotide in patients with acromegaly.

Lanreotide serum levels of 1 ng/ml are able to suppress GH to <5 ng/ml in more than 60% of patients studied. Lanreotide serum levels of 2.5 ng/ml are able to suppress GH to <5 ng/ml in more than 90% of patients studied.

In a population PK analysis in 290 GEP-NET patients receiving lanreotide 120 mg, rapid initial release was seen with mean C_max values of 7.49 ± 7.58 ng/ml reached within the first day after a single injection. Steady-state concentrations were reached after 5 injections of lanreotide 120 mg every 28 days and were sustained up to the last assessment (up to 96 weeks after the first injection). At steady-state the mean C_max values were 13.9 ± 7.44 ng/ml and the mean trough serum levels were 6.56 ± 1.99 ng/ml. The mean apparent terminal half-life was 49.8 ± 28.0 days.

Renal/Hepatic impairment

Subjects with severe renal impairment show an approximately 2-fold decrease in total serum clearance of lanreotide, with a consequent increase in half-life and AUC. In subjects with moderate to severe hepatic impairment, a reduction in clearance was observed (30%). Volume of distribution and mean residence time increased in subjects with all degrees of hepatic insufficiency.

No effect on clearance of lanreotide was observed in a population PK analysis of GEP-NET patients including 165 with mild and moderate renal impairment (106 and 59 respectively) treated with lanreotide. GEP-NET patients with severely impaired renal function were not studied.

No GEP-NET patients with hepatic impairment (as per Child-Pugh score) were studied.

It is not necessary to alter the starting dose in patients with renal or hepatic impairment, as lanreotide serum concentrations in these populations are expected to be well within the range of serum concentrations safely tolerated in healthy subjects.

Elderly patients

Elderly subjects show an increase in half-life and mean residence time compared with healthy young subjects. It is not necessary to alter the starting dose in elderly patients, as lanreotide serum concentrations in this population are expected to be well within the range of serum concentrations safely tolerated in healthy subjects.

In a population PK analysis of GEP-NET patients including 122 aged 65 to 85 years, no effect of age on clearance and volume of distribution of lanreotide was observed.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

In carcinogenic bioassay studies conducted in rats and mice, no systemic neoplastic changes were observed at doses in excess of those achieved in humans at therapeutic doses. Increased incidence of subcutaneous tumours were observed at the injection sites likely due to the increased dose frequency in animals (daily) compared to monthly dosing in humans and therefore may not be clinically relevant.

In in vitro and in vivo standard battery tests, lanreotide did not show any genotoxic potential.