Mechanism of Action
Lanreotide, the active component of Somatuline Depot is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin.
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. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions.
The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients [ see Clinical Studies (14) ]. In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Somatuline Depot, plasma GH levels fall rapidly and are maintained for at least 28 days.
Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits post-prandial secretion of pancreatic polypeptide, gastrin and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in post-prandial insulin secretion, resulting in transient, mild glucose intolerance.
Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity.
Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects [ see Warnings and Precautions (5) ].
In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow, but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide.
In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21 day) of lanreotide, serum glucose concentrations were temporarily decreased by 20-30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only [ see Warnings and Precautions (5) ].
Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis.
Somatuline Depot is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the blood stream.
After a single deep, subcutaneous administration, the mean absolute bioavailability of Somatuline Depot in healthy subjects was 73.4, 69.0 and 78.4%, for the 60, 90 and 120 mg doses, respectively. Mean Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and Cmax, and showed high inter-subject variability. Somatuline Depot showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL with 60 mg.
In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of Somatuline Depot between 60 and 120 mg linear pharmacokinetics were observed in acromegalic patients. At steady state mean Cmax values were 3.8 ± 0.5, 5.7 ± 1.7 and 7.7 ± 2.5 ng/mL increasing linearly with dose. The mean accumulation ratio index was 2.7 which is in line with the range of values for the half life of Somatuline Depot. The steady-state trough serum lanreotide concentrations in patients receiving Somatuline Depot every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60, 90 and 120 mg doses respectively. A limited initial burst effect and a low peak to trough fluctuation (81% to 108%) of the serum concentration at the plateau was observed.
For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1 and 4.0 ± 1.4 ng/mL, respectively).
Somatuline Depot has not been studied in special populations. For completeness, information on studies with an immediate-release formulation (IRF) of lanreotide administered intravenously is provided. A lthough some changes in elimination or distribution have been observed after IRF administration, no changes in the apparent half-life are expected with Somatuline Depot as the terminal phase is controlled by the release of lanreotide from the formulation.
Subjects with end-stage renal disease requiring dialysis showed an approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2-fold increase in half-life and AUC.
Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects.
In moderately to severely hepatically-impaired subjects, a 30% reduction in clearance of lanreotide was observed.
Patients with moderate to severe renal impairment or moderate to severe hepatic impairment should begin treatment with Somatuline Depot 60 mg.
In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion.
Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide acetate at 0.5, 1.5, 5, 10 and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30mg/kg/day resulting in exposures 3-times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide acetate at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant.
Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay.
Subcutaneous dosing (30mg/kg/2 wks) before mating and continuing into gestation in rats at doses 5 times the human clinical exposure (120 mg every 4 weeks) based on mg/m2 had reduced fertility. Gestation length was statistically significantly increased suggesting some delay in parturition at 3 times human exposure. The reduction in fertility in non-acromegalic animals is likely related to the pharmacologic activity (decreased growth hormone secretion) of lanreotide acetate.