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 GH and of peptides and serotonin produced within the gastroenteropancreatic (GEP) endocrine system.
In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin, 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 hypoglycemia; postprandial release of insulin, glucagon, gastrin, other peptides of the GEP 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 preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (ie, 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 eg, 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 tumor volume reduction of >20% in a significant proportion (50%) of patients.
For patients with functional tumours of the gastroenteropancreatic endocrine system, treatment with Sandostatin LAR provides continuous control of symptoms related to the underlying disease. The effect of octreotide in different types of gastroenteropancreatic tumours are as follows:
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.
The biochemical characteristics 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 eg, hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. In some patients, computer 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.
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 as 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 of plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.
Although therapy with proton pump inhibitors or H2
-receptor-blocking agents controls the recurrent peptic ulceration which results from chronic gastrin-stimulated hypersecretion of gastric acid, such control may be incomplete. Diarrhoea may also be a prominent symptom not alleviated in all patients by this therapy. Octreotide alone or in conjunction with proton pump inhibitors or H2
-receptor antagonists may reduce gastric acid hypersecretion and improve symptoms, including diarrhoea. Other symptoms possibly due to peptide production by the tumour eg, flushing, may also be relieved. Plasma gastrin levels fall in some patients.
Administration of octreotide produces a fall in circulating immunoreactive insulin. In patients with operable tumours, octreotide may help to restore and maintain normoglycaemia preoperatively. In patients with inoperative benign or malignant tumours, glycaemic control may be improved even without concomitant sustained reduction in circulating insulin levels.
These rare tumours are characterised by production of GH-releasing factor (GRF) alone or in conjunction with other active peptides. Octreotide produces improvement in the features and symptoms of the resultant acromegaly. This is probably due to inhibition of GRF and GH secretion, and a reduction in pituitary enlargement may follow.
Advanced Neuroendocrine Tumors of the Midgut or Unknown Primary Tumor Location
: A phase III, randomized, double-blind, placebo-controlled study (PROMID) demonstrated that Sandostatin LAR inhibits tumor growth in patients with advanced neuroendocrine tumors of the midgut.
85 patients were randomized to receive Sandostatin LAR 30 mg every 4 weeks (n = 42) or placebo (n = 43) for 18 months, or until tumor progression or death.
Main inclusion criteria were: Treatment naive; histologically confirmed; locally inoperable or metastatic well-differentiated; functionally active or inactive neuroendocrine tumors/carcinomas; with primary tumor 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 tumor progression or tumor-related death (TTP).
In the intent-to-treat analysis population (ITT) (all randomized patients), 26 and 41 progressions or tumor-related deaths were seen in the Sandostatin LAR and placebo groups, respectively (HR = 0.32; 95% CI, 0.19-0.55; p-value =.000015).
In the conservative ITT (cITT) analysis population in which 3 patients were censored at randomization, 26 and 40 progressions or tumor-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 tumor progression was 14.3 months (95% CI, 11 to 28.8 months) in the Sandostatin LAR group and 6 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, tumor progression or tumor-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). (See figure and table.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Treatment effect was similar in patients with functionally active (HR = 0.23; 95% CI, 0.09-0.57) and inactive tumors (HR = 0.25; 95% CI, 0.10 to 0.59).
After 6 months of treatment, stable disease was observed in 66% 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.
After single IM injection of Sandostatin LAR, the serum octreotide concentration reaches a transient initial peak within 1 hr after administration, followed by a progressive decrease to a low undetectable octreotide level within 24 hrs. After this initial peak on day 1, octreotide remains at subtherapeutic levels in the majority of the patients in the following 7 days. Thereafter, octreotide concentrations increase again and reach plateau concentrations around day 14 and remain relatively constant during the following 3-4 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, 20 and 30 mg Sandostatin LAR amount to 358, 926 and 1710 ng/L, respectively. Steady-state octreotide serum concentrations, reached after 3 injections at 4-week intervals, are higher by a factor of approximately 1.6-1.8 and amount to 1557 and 2384 ng/L after multiple injections of 20 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, 20 and 30 mg of Sandostatin LAR given at 4-week intervals also increased linearly with dose and were 1231 (894), 2620 (2270) and 3928 (3010) 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 SC 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.
Toxicology: Preclinical Safety Data: Acute Toxicity:
Acute toxicity studies of octreotide in mice revealed LD50
values of 72 mg/kg by the IV route and of 470 mg/kg by the SC route. The acute IV LD50
value of octreotide in rats was determined at 18 mg/kg. Octreotide acetate was well tolerated by dogs receiving up to 1 mg/kg BW by IV bolus injection.
In a repeat-dose study performed in rats by IM injection of 2.5 mg Sandostatin LAR in 50-mg microspheres every 4 weeks for 21 weeks, with necropsy at 26 weeks, no drug-related necropsy findings were observed. The only histopathological findings considered to be of significance were at the injection site in treated and control animals, where the microspheres had provoked a reversible granulomatous myositis. After a single IM injection of Sandostatin LAR in rats and rabbits, biodegradation of microspheres was complete by day 75 after injection in both species.
Octreotide and/or its metabolites were devoid of mutagenic potential when investigated in vitro
in validated bacterial and mammalian cell test systems. Increased frequencies of chromosomal changes were observed in V79 Chinese hamster cells in vitro
, albeit at high and cytotoxic concentrations only. Chromosomal aberrations were however not increased in human lymphocytes incubated with octreotide acetate in vitro
. In vivo
, no clastogenic activity was observed in the bone marrow of mice treated with octreotide IV (micronucleus test) and no evidence of genotoxicity was obtained in male mice using a DNA repair assay on sperm heads. The microspheres were devoid of mutagenic potential when tested in a validated in vitro
In studies in rats in which SC Sandostatin at daily doses up to 1.25 mg/kg body weight were administered, fibrosarcomas were observed, predominantly in a number of male animals, at the SC injection site after 52, 104 and 113/116 weeks. Local tumours also occurred in the control rats, however, development of these tumours was attributed to disordered fibroplasia produced by sustained irritant effects at the injection sites, enhanced by the acidic lactic acid/mannitol vehicle. This nonspecific tissue reaction appeared to be particular to rats.
Neoplastic lesions were observed neither in mice receiving daily SC injections of Sandostatin at doses up to 2 mg/kg for 98 weeks, nor in dogs which were treated with daily SC doses of the drug for 52 weeks.
The 116 week carcinogenicity study in rats with SC Sandostatin also revealed uterine endometrial adenocarcinomas, their incidence reaching statistical significance at the highest SC dose level of 1.25 mg/kg/day. The finding was associated with an increased incidence of endometritis, a decreased number of ovarian corpora lutea, a reduction in mammary adenomas and the presence of uterine glandular and luminal dilation, suggesting a state of hormonal imbalance. The available information clearly indicates that the findings of endocrine-mediated tumours in rats are species-specific and are not relevant for the use of the drug in humans.
Fertility as well as pre-, peri- and postnatal studies in female rats revealed no adverse effects on reproductive performance and development of the offspring, when SC doses of up to 1 mg/kg body weight/day were administered. Some retardation of the physiological growth noted in pups was transient and attributable to GH inhibition brought about by excessive pharmacodynamic activity.