Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Antigrowth hormones, ATC code: H01C B03.
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 SSTR1, 3, and 4. Activity at human SSTR 2 and 5 is the primary mechanism believed responsible for GH inhibition.
Its marked selectivity for the secretion of growth hormone compared to that of insulin, makes this a product suited to the treatment of acromegaly.
By inhibiting the synthesis of thyroid stimulating hormone (TSH), lanreotide normalised also the thyroid function on patient with thyrotropin-secreting adenomas.

Furthermore, the inhibitory action of lanreotide on intestinal exocrine secretion, digestive hormones and cellular proliferation mechanisms is particularly interesting for its application in the treatment of the symptoms of endocrine digestive tumours, especially carcinoids.
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.
Lanreotide markedly inhibits meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow. Lanreotide significantly reduces prostaglandin E1- stimulated jejunal hydroelectrolytic secretion (water, sodium, potassium and chloride).
Lanreotide reduces prolactin levels in acromegalic patients treated long term.
Lanreotide is clearly more active than natural somatostatin and shows a much longer duration of action.
A randomised, placebo controlled study has investigated the effects of lanreotide PR 30 mg administration every 10 days, on top of concomitant treatment regimen including intravenous corticoids, proton-pump inhibitors, antispasmodics, antiemetics and analgesics in 80 patients with upper intestinal obstruction of malignant origin due to confirmed peritoneal carcinomatosis in palliative care, having at least 2 vomiting episodes per day or a nasogastric tube and for whom, according to recent surgical advice, surgery was inappropriate. Patients having a bowel obstruction which could be explained by a non- malignant cause were excluded from the study.

The primary objective was to assess the proportion of responders 7 days after a single injection of lanreotide PR 30mg versus placebo. Treatment response was defined as 1 or less vomiting episode per day for at least 3 consecutive days or no vomiting recurrence for at least 3 consecutive days for subjects in whom nasogastric tube had been removed.

In the Intent-to-Treat [ITT] population, when based on subject diary record cards (DRC) assessed at day 7, the responders rate was more favourable for lanreotide than placebo although not statistically significant (41.9% [18/43] versus 29.7% [11/37], odds ratio=1.75 [95% CI 0.68, 4.49, p=0.24]).

In the Per Protocol (PP) population a significantly higher responders' rate, based on DRC data, was observed for lanreotide when compared to placebo (57.7% [15/26] and 30.4% [7/23], respectively [odds ratio=3.60, 95% CI 1.03, 12.62, p=0.045]).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
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 were excreted in urine and less than 0.5% were recovered unchanged in faeces, indicating some biliary excretion.
The plasma profile of a single dose of SOMATULINE PR 30mg administered intramuscularly in healthy volunteers is characterised by an initial rapid release phase, corresponding to the release of peptide bound to the surface of the microspheres, and then by a second release phase, followed by a very slow decrease induced by the prolonged release of the active substance captured in the micro particles constituting the drug product.
After an initial serum concentration peak of 8.5 ± 4.7 ng/ml obtained between 1 and 2 h after drug administration, serum levels decrease during 1-3 days and then rise from day 3 to 5 until day 14-21 showing a “pseudo plateau” with most of the serum levels around 1ng/mL during this period of time.
This prolonged release behaviour is described by a mean residence time of 15.0 ± 1.6 days and a half-life of 5.0 ± 2.3 days.
The pharmacokinetic profile in acromegalic patients after a single administration of SOMATULINE PR 30mg is comparable to that obtained in healthy volunteers.
Pharmacokinetic profile after repeated administration has been also studied in acromegalic patients. Steady state levels is obtained after the 4th consecutive dose presenting a peak of 10.9 ± 4.4 ng/mL around 2 hours after administration and then a “pseudo plateau” followed by a first order kinetics. The mean minimum and average serum concentrations at steady state are 2.2 ± 0.7 and 2.8 ± 0.8 ng/mL respectively. No relevant accumulation is observed (Rac = 2.2).
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.
It is not necessary to modify the starting dose in patients with renal or hepatic impairment, as lanreotide serum concentrations in these populations are expected to be maintained 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 modify the starting dose in elderly patients, as lanreotide serum concentrations in this population are expected to be maintained within the range of serum concentrations safely tolerated in healthy subjects.