Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.   Pharmacodynamic properties

Pharmacotherapeutic group: Somatostatin and analogues, ATC code: H01CB02 
Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a considerably prolonged duration of action. It inhibits pathologically increased secretion of growth hormone (GH) and of peptides and serotonin produced within the GEP endocrine system.

In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin is, with greater selectivity for GH and glucagon suppression.
In healthy subjects octreotide, like somatostatin, has been shown to inhibit: • release of GH stimulated by arginine, exercise- and insulin-induced hypoglycaemia, • post-prandial release of insulin, glucagon, gastrin, other peptides of the GEP endocrine system, and arginine-stimulated release of insulin and glucagon,
• thyrotropin-releasing hormone (TRH)-stimulated release of thyroid-stimulating hormone (TSH).

Unlike somatostatin, octreotide inhibits GH secretion preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. GH in patients with acromegaly).

In patients with acromegaly, Sandostatin LAR, a galenical formulation of octreotide suitable for repeated administration at intervals of 4 weeks, delivers consistent and therapeutic octreotide serum concentrations thus consistently lowering GH and normalising IGF 1 serum concentrations in the majority of patients. In most patients, Sandostatin LAR markedly reduces the clinical symptoms of the disease, such as headache, perspiration, paraesthesia, fatigue, osteoarthralgia and carpal tunnel syndrome. In previously untreated acromegaly patients with GH-secreting pituitary adenoma, Sandostatin LAR treatment resulted in a tumour volume reduction of >20% in a significant proportion (50%) of patients.

In individual patients with GH-secreting pituitary adenoma, Sandostatin LAR was reported to lead to shrinkage of the tumour (prior to surgery). However, surgery should not be delayed.

For patients with functional tumours of the gastro-entero-pancreatic endocrine system, treatment with Sandostatin LAR provides continuous control of symptoms related to the underlying disease. The effect of octreotide in different types of gastro-entero-pancreatic tumours are as follows:

Carcinoid tumours

Administration of octreotide may result in improvement of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5 hydroxyindole acetic acid.

VIPomas

The biochemical characteristic of these tumours is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of octreotide results in alleviation of the severe secretory diarrhoea typical of the condition, with consequent improvement in quality of life.
This is accompanied by an improvement in associated electrolyte abnormalities, e.g.
hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. In some patients, computed tomography scanning suggests a slowing or arrest of progression of the tumour, or even tumour shrinkage, particularly of hepatic metastases.
Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.

Glucagonomas

Administration of octreotide results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of octreotide on the state of mild diabetes mellitus which frequently occurs is not marked and, in general, does not result in a reduction of requirements for insulin or oral hypoglycaemic agents. Octreotide produces improvement of diarrhoea, and hence weight gain, in those patients affected. Although administration of octreotide often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.

Gastrinomas/Zollinger-Ellison syndrome

Therapy with proton pump inhibitors or H2 receptor blocking agents generally controls gastric acid hypersecretion. However, diarrhoea, which is also a prominent symptom, may not be adequately alleviated by proton pump inhibitors or H2 receptor blocking agents. Sandostatin LAR can help to further reduce gastric acid hypersecretion and improve symptoms, including diarrhoea, as it provides suppression of elevated gastrin levels, in some patients.

Insulinomas

Administration of octreotide produces a fall in circulating immunoreactive insulin. In patients with operable tumours, octreotide may help to restore and maintain normoglycemia pre- operatively. In patients with inoperative benign or malignant tumours, glycaemic control may be improved even without concomitant sustained reduction in circulating insulin levels.
Advanced neuroendocrine tumours of the midgut or of unknown primary origin where non-midgut sites of origin have been excluded
A Phase III, randomised, double-blind, placebo-controlled study (PROMID) demonstrated that Sandostatin LAR inhibits tumour growth in patients with advanced neuroendocrine tumours of the midgut. 85 patients were randomised to receive Sandostatin LAR 30 mg every 4 weeks (n=42) or placebo (n=43) for 18 months, or until tumour progression or death.

Main inclusion criteria were: treatment naïve; histologically confirmed; locally inoperable or metastatic well-differentiated; functionally active or inactive neuroendocrine tumours/carcinomas; with primary tumour located in the midgut or unknown origin believed to be of midgut origin if a primary within the pancreas, chest, or elsewhere was excluded.

The primary endpoint was time to tumour progression or tumour-related death (TTP).

In the intent-to-treat analysis population (ITT) (all randomised patients), 26 and 41 progressions or tumour-related deaths were seen in the Sandostatin LAR and placebo groups, respectively (HR = 0.32; 95% CI, 0.19 to 0.55; p-value =.000015).

In the conservative ITT (cITT) analysis population in which 3 patients were censored at randomization, 26 and 40 progressions or tumour-related deaths were observed in the Sandostatin LAR and placebo groups, respectively (HR=0.34; 95% CI, 0.20 to 0.59; p-value =.000072; Fig 1). Median time to tumour progression was 14.3 months (95% CI, 11.0 to 28.8 months) in the Sandostatin LAR group and 6.0 months (95% CI, 3.7 to 9.4 months) in the placebo group.

In the per-protocol analysis population (PP) in which additional patients were censored at end study therapy, tumour progression or tumour-related death was observed in 19 and 38 Sandostatin LAR and placebo recipients, respectively (HR = 0.24; 95% CI, 0.13 to 0.45; p- value =.0000036).
Figure 1       Kaplan-Meier estimates of TTP comparing Sandostatin LAR with placebo (conservative ITT population)



Table 3 TTP results by analysis populations

TTP Events                     Median TTP months [95% C.I.]          HR [95% C.I.] p-value *
Sandostatin         Placebo      Sandostatin          Placebo
LAR                                 LAR
ITT               26               41            NR                 NR            0.32 [95% CI, 0.19 to
0.55] P=0.000015 cITT               26              40             14.3         6.0                0.34 [95% CI, 11.0 [95% CI, 3.7 to   [95% CI, 0.20 to to 28.8]       9.4]        0.59] P=0.000072
PP                 19              38             NR           NR                 0.24 [95% CI, 0.13 to
0.45] P=0.0000036
NR=not reported; HR=hazard ratio; TTP=time to tumour progression; ITT=intention to treat; cITT=conservative ITT; PP=per protocol
*Logrank test stratified by functional activity

Treatment effect was similar in patients with functionally active (HR = 0.23; 95% CI, 0.09 to 0.57) and inactive tumours (HR = 0.25; 95% CI, 0.10 to 0.59).

After 6 months of treatment, stable disease was observed in 67% of patients in the Sandostatin LAR group and 37% of patients in the placebo group.

Based on the significant clinical benefit of Sandostatin LAR observed in this pre-planned interim analysis the recruitment was stopped.

The safety of Sandostatin LAR in this trial was consistent with its established safety profile.

Pharmacokinetic Properties

5.2.   Pharmacokinetic properties
After single i.m. injections of Sandostatin LAR, the serum octreotide concentration reaches a transient initial peak within 1 hour after administration, followed by a progressive decrease to a low undetectable octreotide level within 24 hours. After this initial peak on day 1, octreotide remains at sub-therapeutic levels in the majority of the patients for the following 7 days.
Thereafter, octreotide concentrations increase again, and reach plateau concentrations around day 14 and remain relatively constant during the following 3 to 4 weeks. The peak level during day 1 is lower than levels during the plateau phase and no more than 0.5% of the total drug release occurs during day 1. After about day 42, the octreotide concentration decreases slowly, concomitant with the terminal degradation phase of the polymer matrix of the dosage form.

In patients with acromegaly, plateau octreotide concentrations after single doses of 10 mg, 20 mg and 30 mg Sandostatin LAR amount to 358 ng/L, 926 ng/L, and 1,710 ng/L, respectively.
Steady-state octreotide serum concentrations, reached after 3 injections at 4 week intervals, are higher by a factor of approximately 1.6 to 1.8 and amount to 1,557 ng/L and 2,384 ng/L after multiple injections of 20 mg and 30 mg Sandostatin LAR, respectively.

In patients with carcinoid tumours, the mean (and median) steady-state serum concentrations of octreotide after multiple injections of 10 mg, 20 mg and 30 mg of Sandostatin LAR given at 4 week intervals also increased linearly with dose and were 1,231 (894) ng/L, 2,620 (2,270) ng/L and 3,928 (3,010) ng/L, respectively.

No accumulation of octreotide beyond that expected from overlapping release profiles occurred over a duration of up to 28 monthly injections of Sandostatin LAR.

The pharmacokinetic profile of octreotide after injection of Sandostatin LAR reflects the release profile from the polymer matrix and its biodegradation. Once released into the systemic circulation, octreotide distributes according to its known pharmacokinetic properties, as described for s.c. administration. The volume of distribution of octreotide at steady-state is 0.27 L/kg and the total body clearance is 160 mL/min. Plasma protein binding amounts to 65% and essentially no drug is bound to blood cells.

Pharmacokinetic data with limited blood sampling in pediatric patients with hypothalamic obesity, aged 7–17 years, receiving Sandostatin LAR 40 mg once monthly, showed mean octreotide trough plasma concentrations of 1,395 ng/L after the first injection and of 2,973 ng/L at steady state. A high inter-subject variability is observed.

Steady-state trough octreotide concentrations were not correlated with age and BMI, but moderately correlated with body weight (52.3–133 kg) and was significantly different between male and female patients, i.e. about 17% higher for female patients.