Somatuline Depot

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

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 SSTR2 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]. 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 postprandial secretion of pancreatic polypeptide, gastrin, and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in postprandial 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].

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].

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.

Pharmacokinetics

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 bloodstream.

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 mg, 90 mg, and 120 mg doses, respectively. Mean C max 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 at 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.

Acromegaly

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 C max 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 mg, 90 mg, 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 were 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).

Pharmacokinetic data from studies evaluating extended dosing use of SOMATULINE DEPOT 120 mg demonstrated mean steady-state, C min values between 1.6 and 2.3 ng/mL for the 8-and 6-week treatment interval, respectively.

Gastroenteropancreatic Neuroendocrine Tumors

In patients with GEP-NETs treated with SOMATULINE DEPOT 120 mg every 4 weeks, steady state concentrations were reached after 4 to 5 injections and the mean trough serum lanreotide concentrations at steady state ranged from 5.3 to 8.6 ng/mL.

Specific Populations

SOMATULINE DEPOT has not been studied in specific populations. However, the pharmacokinetics of lanreotide in renal impaired, hepatic impaired, and geriatric subjects were evaluated after IV administration of lanreotide immediate release formulation (IRF) at 7 mcg/kg dose.

Geriatric

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. Age has no effect on clearance of lanreotide based on population PK analysis in patients with GEP-NET which included 122 patients aged 65 to 85 years with neuroendocrine tumors.

Renal Impairment

An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2-fold increase in half-life and AUC was observed. Patients with acromegaly and with moderate to severe renal impairment should begin treatment with SOMATULINE DEPOT 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of SOMATULINE DEPOT 120 mg every 6 or 8 weeks.

Mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment has no effect on clearance of lanreotide in patients with GEP-NET based on population PK analysis which included 106 patients with mild and 59 patients with moderate renal impairment treated with SOMATULINE DEPOT. GEP-NET patients with severe renal impairment (CLcr < 30 mL/min) were not studied.

Hepatic Impairment

In subjects with moderate to severe hepatic impairment, a 30% reduction in clearance of lanreotide was observed. Patients with acromegaly and with moderate to severe hepatic impairment should begin treatment with SOMATULINE DEPOT 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of SOMATULINE DEPOT 120 mg every 6 or 8 weeks.

The effect of hepatic impairment on clearance of lanreotide has not been studied in patients with GEP-NET.

Clinical Studies

Acromegaly

The effect of SOMATULINE DEPOT on reducing GH and IGF-levels and control of symptoms in patients with acromegaly was studied in two long-term, multiple-dose, randomized, multicenter studies.

Study 1

This one-year study included a 4-week, double-blind, placebo-controlled phase; a 16-week single-blind, fixed-dose phase; and a 32-week, open-label, dose-titration phase. Patients with active acromegaly, based on biochemical tests and medical history, entered a 12-week washout period if there was previous treatment with a somatostatin analog or a dopaminergic agonist.

Upon entry, patients were randomly allocated to receive a single, deep subcutaneous injection of SOMATULINE DEPOT 60 mg, 90 mg, or 120 mg or placebo. Four weeks later, patients entered a fixed-dose phase where they received 4 injections of SOMATULINE DEPOT followed by a dose-titration phase of 8 injections for a total of 13 injections over 52 weeks (including the placebo phase). Injections were given at 4-week intervals. During the dose-titration phase of the study, the dose was titrated twice (every fourth injection), as needed, according to individual GH and IGF-1 levels.

A total of 108 patients (51 males, 57 females) were enrolled in the initial placebo-controlled phase of the study. Half (54/108) of the patients had never been treated with a somatostatin analog or dopamine agonist, or had stopped treatment for at least 3 months prior to their participation in the study and were required to have a mean GH level > 5 ng/mL at their first visit. The other half of the patients had received prior treatment with a somatostatin analog or a dopamine agonist before study entry and at study entry were required to have a mean GH concentration > 3 ng/mL and at least a 100% increase in mean GH concentration after washout of medication.

One hundred and seven (107) patients completed the placebo-controlled phase, 105 patients completed the fixed-dose phase, and 99 patients completed the dose-titration phase. Patients not completing withdrew due to adverse events (5) or lack of efficacy (4).

In the double-blind phase of study 1, a total of 52 (63%) of the 83 lanreotide-treated patients had a > 50% decrease in mean GH from baseline to Week 4, including 52%, 44%, and 90% of patients in the 60 mg, 90 mg, and 120 mg groups, respectively, compared to placebo (0%, 0/25). In the fixed-dose phase at Week 16, 72% of all 107 lanreotide-treated patients had a decrease from baseline in mean GH of > 50%, including 68% (23/34), 64% (23/36), and 84% (31/37) of patients in the 60 mg, 90 mg, and 120 mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained for the duration of the study (see Table 4).

Table 4: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 1

    Baseline
N=107
Before Titration 1 (16 weeks)
N=107
Before Titration 2 (32 weeks)
N=105
Last Value Available*
N=107
GH
≤ 5.0 ng/mL Number of Responders (%) 20 (19%) 72 (67%) 76 (72%) 74 (69%)
≤ 2.5 ng/mL Number of Responders (%) 0 (0%) 52 (49%) 59 (56%) 55 (51%)
≤ 1.0 ng/mL Number of Responders (%) 0 (0%) 15 (14%) 18 (17%) 17 (16%)
Median GH ng/mL 10.27 2.53 2.20 2.43
GH Reduction Median % Reduction -- 75.5 78.2 75.5
IGF-1
Normal3 Number of 9 58 57 62
  Responders (%) (8%) (54%) (54%) (58%)
Median IGF-1 ng/mL 775.0 332.01 316.52 326.0
IGF-1 Reduction Median % Reduction -- 52.31 54.52 55.4
IGF-1 Normal3 +GH ≤ 2.5 ng/mL Number of Responders (%) 0 (0%) 41 (38%) 46 (44%) 44 (41%)
1n=105,
2n=102,
3Age-adjusted,
*Last Observation Carried Forward

Study 2

This was a 48-week, open-label, uncontrolled, multicenter study that enrolled patients who had an IGF-1 concentration ≥ 1.3 times the upper limit of the normal age-adjusted range. Patients receiving treatment with a somatostatin analog (other than SOMATULINE DEPOT) or a dopaminergic agonist had to attain this IGF1 concentration after a washout period of up to 3 months.

Patients were initially enrolled in a 4-month, fixed-dose phase where they received 4 deep subcutaneous injections of SOMATULINE DEPOT 90 mg, at 4-week intervals. Patients then entered a dose-titration phase where the dose of SOMATULINE DEPOT was adjusted based on GH and IGF-1 levels at the beginning of the dose-titration phase and, if necessary, again after another 4 injections. Patients titrated up to the maximum dose (120 mg) were not allowed to titrate down again.

A total of 63 patients (38 males, 25 females) entered the fixed-dose phase of the trial and 57 patients completed 48 weeks of treatment. Six patients withdrew due to adverse reactions (3), other reasons (2), or lack of efficacy (1).

After 48 weeks of treatment with SOMATULINE DEPOT at 4-week intervals, 43% (27/63) of the acromegalic patients in this study achieved normal age-adjusted IGF-1 concentrations. Mean IGF-1 concentrations after treatment completion were 1.3 ± 0.7 times the upper limit of normal compared to 2.5 ± 1.1 times the upper limit of normal at baseline.

The reduction in IGF-1 concentrations over time correlated with a corresponding marked decrease in mean GH concentrations. The proportion of patients with mean GH concentrations < 2.5 ng/mL increased significantly from 35% to 77% after the fixed-dose phase and 85% at the end of the study. At the end of treatment, 24/63 (38%) of patients had both normal IGF-1 concentrations and a GH concentration of ≤ 2.5 ng/mL (see Table 5) and 17/63 patients (27%) had both normal IGF-1 concentrations and a GH concentration of < 1 ng/mL.

Table 5: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 2

    Baseline
N=63
Before Titration 1(12 wks)
N=63
Before Titration 2(28 wks)
N=59
Last Value Available*
N=63
IGF-1
Normal1 Number of Responders (%) 0(0%) 17(27%) 22(37%) 27(43%)
Median IGF-1 ng/mL 689.0 382.0 334.0 317.0
IGF-1 Reduction Median % Reduction -- 41.0 51.0 50.3
GH
≤ 5.0 ng/mL Number of Responders (%) 40 (64%) 59 (94%) 57 (97%) 62 (98%)
≤ 2.5 ng/mL Number of Responders (%) 21 (33%) 47 (75%) 47 (80%) 54 (86 %)
≤ 1.0 ng/mL Number of Responders (%) 8 (13%) 19 (30%) 18 (31%) 28 (44%)
Median GH ng/mL 3.71 1.65 1.48 1.13
GH Reduction Median % Reduction -- 63.2 66.7 78.62
IGF-1 normal1 +GH ≤ 2.5 ng/mL Number of Responders (%) 0 (0%) 14 (22%) 20 (34%) 24 (38%)
1Age-adjusted,
2N= 62,
*Last Observation Carried Forward

Examination of age and gender subgroups did not identify differences in response to SOMATULINE DEPOT among these subgroups. The limited number of patients in the different racial subgroups did not raise any concerns regarding efficacy of SOMATULINE DEPOT in these subgroups.

Gastroenteropancreatic Neuroendocrine Tumors

The efficacy of SOMATULINE DEPOT was established in a multicenter, randomized, double-blind, placebo-controlled trial of 204 patients with unresectable, well or moderately differentiated, metastatic or locally advanced, gastroenteropancreatic neuroendocrine tumors. Patients were required to have non-functioning tumors without hormone-related symptoms. Patients were randomized 1:1 to receive SOMATULINE DEPOT 120 mg (n=101) or placebo (n=103) every 4 weeks until disease progression, unacceptable toxicity or a maximum of 96 weeks of treatment. Randomization was stratified by the presence or absence of prior therapy and by the presence or absence of disease progression within 6 months of enrollment. The major efficacy outcome measure was progression-free survival (PFS), defined as time to disease progression as assessed by central independent radiological review using the Response Evaluation Criteria in Solid Tumors (RECIST 1.0), or death.

The median patient age was 63 years (range 30-92 years) and 95% were Caucasian. Disease progression was present in nine of 204 patients (4.4%) in the 6 months prior to enrollment and twenty-nine patients (14%) received prior chemotherapy. Ninety-one patients (45%) had primary sites of disease in the pancreas, with the remainder originating in the midgut (35%), hindgut (7%), or unknown primary location (13%). The majority (69%) of the study population had grade 1 tumors. Baseline prognostic characteristics were similar between arms with one exception; there were 39% of patients in the SOMATULINE DEPOT arm and 27% of patients in the placebo arm who had hepatic involvement by tumor of > 25%.

Patients on the SOMATULINE DEPOT arm had a statistically significant improvement in progression-free survival compared to patients receiving placebo (see Table 6 and Figure 1).

Table 6: Efficacy Results in Study 3

  SOMATULINE DEPOT
n = 101
Placebo
n = 103
Number of Events (%) 32 (31.7%) 60 (58.3%)
Median PFS (months)(95% CI) NE1 (NE, NE) 16.6 (11.2, 22.1)
HR (95% CI) 0.47 (0.30, 0.73)2
Log-rank p-value < 0.001
1 NE = not reached at 22 months
2 Hazard Ratio is derived from a Cox stratified proportional hazards model

Figure 1: Kaplan-Meier Curves of Progression-Free Survival

Kaplan-Meier Curves of Progression-Free Survival - Illustration

Last reviewed on RxList: 1/5/2015
This monograph has been modified to include the generic and brand name in many instances.

A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.