Pharmacology: Mechanism of action (MOA): 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 Sandostatin has been shown to inhibit: the release of GH stimulated by arginine, exercise- and insulin-induced hypoglycemia; postprandial 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 acromegalic patients Sandostatin lowers plasma levels of GH and IGF-1. A GH reduction by 50% or more occurs in up to 90% patients, and a reduction of serum GH to < 5 ng/mL can be achieved in about half of the cases. In most patients Sandostatin markedly reduces the clinical symptoms of the disease, such as headache, skin and soft tissue swelling, hyperhidrosis, arthralgia, paresthesia. In patients with a large pituitary adenoma, Sandostatin treatment may result in some shrinkage of the tumor mass.
In patients with functional tumors of the GEP endocrine system, Sandostatin, because of its diverse endocrine effects, modifies a number of clinical features. Clinical improvement and symptomatic benefit occur in patients who still have symptoms related to their tumors despite previous therapies, which may include surgery, hepatic artery embolization, and various chemotherapies, e.g. streptozotocin and 5-fluorouracil.
Pharmacodynamics: Sandostatin's effects in the different tumor types are as follows: Carcinoid tumors: Administration of Sandostatin may result in improvement of symptoms, particularly of flush and diarrhea. 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 tumors is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of Sandostatin results in alleviation of the severe secretory diarrhea typical of the condition, with consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, e.g. hypokalemia, 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 tumor, or even tumor 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 Sandostatin results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of Sandostatin 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 hypoglycemic agents. Sandostatin produces improvement of diarrhea, and hence weight gain, in those patients affected. Although administration of Sandostatin 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: 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. Diarrhea may also be a prominent symptom not alleviated by this therapy. Sandostatin alone or in conjunction with proton pump inhibitors or H2-receptor antagonists may reduce gastric acid hypersecretion and improve symptoms, including diarrhea. Other symptoms possibly due to peptide production by the tumor, e.g. flush, may also be relieved. Plasma gastrin levels fall in some patients.
Insulinomas: Administration of Sandostatin produces a fall in circulating immunoreactive insulin, which may, however, be of short duration (about 2 hours). In patients with operable tumors, Sandostatin may help to restore and maintain normoglycaemia pre-operatively. In patients with inoperable benign or malignant tumors, glycemic control may be improved without concomitant sustained reduction in circulating insulin levels.
GRFomas: These rare tumors are characterized by production of GH releasing factor (GRF) alone or in conjunction with other active peptides. Sandostatin 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.
For patients undergoing pancreatic surgery, the peri- and post-operative administration of Sandostatin reduces the incidence of typical postoperative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, postoperative acute pancreatitis).
In patients presenting with bleeding gastro-esophageal varices due to underlying cirrhosis, Sandostatin administration in combination with specific treatment (e.g. sclerotherapy) is associated with better control of bleeding and early re-bleeding, reduced transfusion requirements, and improved 5-day survival. While the precise mode of action of Sandostatin is not fully elucidated, it is postulated that Sandostatin reduces splanchnic blood flow through inhibition of vaso-active hormones (e.g. VIP, glucagon).
Pharmacokinetics: Absorption: After s.c. injection, Sandostatin is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 minutes.
Distribution: The volume of distribution is 0.27 L/kg, and the total body clearance 160 mL/min. Plasma protein binding amounts to 65%. The amount of Sandostatin bound to blood cells is negligible.
Elimination: The elimination half-life after s.c. administration is 100 minutes. After i.v. injection, the elimination is biphasic, with half-lives of 10 and 90 minutes. Most of the peptide is eliminated via the feces, while approximately 32% is excreted unchanged into the urine.
Special patient population: Impaired renal function did not affect the total exposure (AUC) to octreotide administered as s.c. injection.
The elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease.
Toxicology: Non-clinical Safety Data: Repeat-dose toxicity: An initial 26-week i.v. toxicity study in dogs carried out at dose levels of up to 0.5 mg/kg once daily revealed proliferative/degenerative changes in acidophil prolactin-containing cells in the pituitary. Further investigations showed this to be within the physiological range of the species used. Female Rhesus monkeys receiving 0.5 mg/kg twice daily (b.i.d) for 3 weeks failed to reveal pituitary changes, and there were no alterations of basal levels of plasma growth hormone, prolactin, or glucose.
Whereas the acidic vehicle produced inflammation and fibroplasia upon repeated s.c. injection in rats, there was no evidence that octreotide acetate causes delayed-type hypersensitivity reactions when injected intradermally in guinea pigs in 0.1% solution in 0.9% sterile saline.
Genotoxicity: Octreotide and/or its metabolites were devoid of mutagenic potential when investigated in vitro in validated bacterial and mammalian cell test systems. In one study, an increased frequency of chromosomal changes were observed in V79 Chinese hamster cells, albeit at high and cytotoxic concentrations only. Chromosomal aberrations were however not increased in human lymphocytes incubated with octreotide acetate. In vivo, no clastogenic activity was observed in the bone marrow of mice treated with octreotide i.v. (micronucleus test) and no evidence of genotoxicity was obtained in male mice using a DNA repair assay on sperm heads.
Carcinogenicity/chronic toxicity: In rats receiving octreotide acetate at daily doses up to 1.25 mg/kg body weight, fibrosarcomas were observed, predominantly in a number of male animals, at the s.c. injection site after 52, 104 and 113/116 weeks. Local tumors occurred also in the control rats, however development of these tumors was attributed to disordered fibroplasia produced by sustained irritant effects at the injection sites, enhanced by the acidic lactic acid/mannitol vehicle. This non-specific tissue reaction appeared to be particular to rats. Neoplastic lesions were observed neither in mice receiving daily s.c. injections of octreotide at doses up to 2 mg/kg for up to 99 weeks, nor in dogs which were treated with daily s.c. doses of the drug for 52 weeks.
The 116-week carcinogenicity study in rats with s.c. octreotide also revealed uterine endometrial adenocarcinomas, their incidence reaching statistical significance at the highest s.c. dose level of 1.25 mg/kg per 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 tumors in rats are species-specific and are not relevant for the use of the drug in humans.
Reproduction: Reproduction studies have been performed in rats and rabbits at parenteral doses of up to 1 mg/kg body weight per day. Some retardation of the physiological growth was noted in the offspring of rats which was transient and most likely attributable to GH inhibition brought about by excessive pharmacodynamic activity. There was no evidence of teratogenic, embryo/fetal or other reproduction effects due to octreotide.