Somatuline Autogel Mechanism of Action

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues; Somatostatin and analogues. ATC code: H01C B03.
Pharmacology: Pharmacodynamics: Mechanism of action: Lanreotide in 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, 3 and 5, and reduced 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. Its marked selectivity for the secretion of growth hormone compared to that of insulin, makes this a product suited to the treatment of acromegaly.
Lanreotide, 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 inhibits meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow.
Lanreotide reduces prostaglandin E1-stimulated jejunal hydroelectrolytic secretion (water, sodium potassium and chloride).
Lanreotide reduces prolactin levels in acromegalic patients treated long term.
Clinical studies: In an open-label study, Somatuline Autogel 120 mg was administered every 28 days for 48 weeks in 90 previously untreated acromegalic patients diagnosed with pituitary macroadenoma. At week 48, 63% of the patients showed a clinically relevant reduction in tumor volume of ≥20% (which was the primary efficacy endpoint) although statistical significance was not reached (95% CI: 52% - 73%).
The mean percentage reduction of tumour volume was 26.8%, GH levels were below 2.5 μg/L in 77.8% of the patients and IGF-1 levels normalised in 50%. Normalised IGF-1 levels combined with GH levels below 2.5 μg/L were observed in 43.5% of the patients.
Patients reported a relief of acromegaly symptoms such as fatigue (56.5%), excess perspiration (66.1%), arthralgia (59.7%), soft tissue swelling (66.1%) and headache (38.7%).
A reduction in tumor volume and concentrations of GH and IGF-1 was shown from week 12 and was maintained for 48 weeks.
The study excluded patients who were expected to require pituitary surgery or radiotherapy during the study period.
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.
A phase III, 96-week, fixed duration, randomized, double-blind, multi-centre, placebo-controlled trial was conducted in patients with gastroenteropancreatic neuroendocrine tumours to assess the antiproliferative effect of lanreotide.
Patients were randomized 1:1 to receive either Somatuline Autogel 120 mg every 28 days (n=101) or placebo (n=103). Randomization was stratified by previous therapy at entry and the presence/absence of progression at baseline as assessed by RECIST 1.0 (Response Evaluation Criteria in Solid Tumours) during a 3 to 6 months screening phase.
Patients had metastatic and/or locally advanced inoperable disease with histologically confirmed well or moderately well differentiated tumours primarily localized in the pancreas (44.6% patients), midgut (35.8%), hindgut (6.9%) or of other/unknown primary location 12.7%).
69% of patients with GEP-NETs had tumour grade 1 (G1), defined by either a proliferation index Ki67 ≤2% (50.5% of the overall patient population) or a mitotic index <2 mitosis/10 HPF (18.5% of the overall patient population) and 30% of patients with GEP-NETs had tumours in the lower range of grade 2 (G2) (defined by a Ki67 index >2% - ≤10%). Grade was not available in 1% of the patients.
The study excluded patients with G2 GEP-NETs with a higher cellular proliferation index (Ki67 >10% - ≤20%) and G3 GEP neuroendocrine carcinomas (Ki67 index >20%).
Overall, 52.5% of the patients had an hepatic tumour load ≤10%, 14.5% had an hepatic tumour load >10 and ≤25% and 33% had an hepatic tumour load >25%.
The primary endpoint was progression-free survival (PFS) measured as time to either disease progression by RECIST 1.0 or death within 96 weeks after first treatment administration. Analysis of PFS utilized independent centrally-reviewed radiological assessment of progression. (See Table 1 and Figure 1.)

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The beneficial effect of lanreotide in reducing the risk of progression or death was consistent regardless of the location of primary tumour, hepatic tumour load, previous chemotherapy, baseline Ki67, tumour grade or other pre-specified characteristics as shown in Figure 2.
A clinically relevant benefit of treatment with Somatuline Autogel was seen in patients with tumours of pancreatic, midgut and other/unknown origin as in the overall study population. The limited number of patients with hindgut tumours (14/204) contributed to difficulty in interpreting the results in this subgroup. The available data suggested no benefit of lanreotide in these patients. (See Figure 2.)

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Crossover from placebo to open-label Somatuline Autogel, in the extension study, occurred in 45.6% (47/103) of the patients.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Somatuline Autogel in all subsets of the paediatric population in acromegaly and pituitary gigantism (see Dosage & Administration for information on paediatric use). The European Medicines Agency has listed gastroenteropancreatic neuroendocrine tumours (excluding neuroblastoma, neuroganglioblastoma, phaeochromocytoma) on the list of class waivers.
Pharmacokinetics: 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 1.24 hours and mean residence time of 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.
After a deep subcutaneous injection of Somatuline Autogel 60 mg, 90 mg 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. 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 a first order kinetics with a terminal elimination half-life of 23.3, 27.4 and 30.1 days respectively and 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%.
After deep subcutaneous administration of Somatuline Autogel 60 mg, 90 mg and 120 mg to acromegalic patients, lanreotide concentrations increase to achieve average maximum serum concentrations of 1.6, 3.5 and 3.1 ng/ml. 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 through fluctuation index was moderate ranging from 81 to 108%.
Linear pharmacokinetic release profiles were observed after deep subcutaneous administration of Somatuline Autogel 60 mg, 90 mg and 120 mg in acromegalic patients.
In a population PK analysis in 290 GEP-NET patients receiving Somatuline Autogel 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 Somatuline Autogel 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.
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.
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 Somatuline Autogel. 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.
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.
Toxicology: Preclinical safety data: 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.