Octreotide administration

Use of the first-generation somatostatin analog octreotide is limited by its extremely short duration of action and requirement for subcutaneous administration at least three times a day. If a patient s GH level returns to baseline before the end of an 8-hour dosing interval, the frequency of octreotide administration can be increased to every 4 to 6 hours. Most patients require octreotide in doses of 100 to 200 meg three times daily.19,20 To improve patient tolerance to gastrointestinal (GI) adverse effects, start octreotide at 50 meg every 8 hours.20 Assess IGF-I serum concentrations every 2 weeks after initiating therapy to further titrate dose in increments of 50 meg per dose. 

A dopamine agonist alone or in combination with pituitary surgery, radiation therapy, or octreotide administration can be used to treat acromegaly. The doses required are higher than those used to treat hyperprolactinemia. For example, patients with acromegaly require 20-30 mg/d of bromocriptine and seldom respond adequately to bromocriptine alone unless the pituitary tumor secretes prolactin as well as GH. 

Tang LJ, Zipser S, Kang YS. Temporary spontaneous thrombosis of a splenic artery pseudoaneurysm in chronic pancreatitis during intravenous octreotide administration. J Vase Interv Radiol 2005 16(6) 863-6. 

Walters, A.M., Earvin, M., Sadek, S.A. Control of colonic variceal haemorrhage by long-term octreotide administration. Brit. J. Surg. 1994 81 290... 

Both somatostatin and octreotide cause transient increases in mean arterial pressure and mean pulmonary pressure when given intravenously to patients with cirrhosis, more marked with bolus administration than with continuous infusion (5). This may be either direct or mediated by inhibition of gut vasodilatory peptides (SEDA-24, 505 6) and is not usually associated with significant clinical effects. 

Severe hypertension with associated headache, nausea, and vomiting was reported within 2 weeks of administration of octreotide LAR 20 mg in a 26-year-old diabetic woman with autonomic neuropathy (6). Rechallenge with octreotide 75 pg resulted in a transient hypertensive episode lasting 3 hours. 

Atmaca A, Erbas, T. Lipoatrophy induced by subcutaneous administration of octreotide in the treatment of acromegaly. Exp Clin Endocrinol Diabetes 2005 113 340-3. 

Beranek L, Hajdu I, Gardi J, Taishi P, Obal F, Jr., Krueger JM. Central administration of the somatostatin analog octreotide induces captopril-insensitive sleep responses. Am J Physiol 1999 277 R1297-R1304. 

In general, the volume of distribution of the central compartment (Vc), in which peptides and proteins initially distribute after an IVadministration, is typically equal to or slightly larger than the plasma volume of 3-8 L (approximate body water volumes for a 70-kg person interstitial 12 L, intracellular 27 L, intravascular 3 L). Furthermore, the steady-state volume of distribution (Vss) is usually no more than twice the initial volume of distribution, or approximately 14-20 L [13, 37, 43]. This distribution pattern has been described for the somatostatin analogue octreotide (Vc 5.2-10.2 L Vss 18-30 L), and t-PA analogue tenecteplase (Vc 4.2-6.3 L Vss 6.1-9.9 L) [52]. Epoetin-a also has a volume of distribution estimated to be close to the plasma volume at 0.0558 L/kg after an IVadministration to healthy volunteers [53]. Similarly, Vss for darbepoetin-a has been reported as 0.0621 L/kg after an IV administration in patients undergoing dialysis [54], and distribution of thrombopoie-tin has also been reported to be limited to the plasma volume (-3 L) [55]. 

Octreotide was also administered to juvenile pigs with or without TMC60 at a pH of 7.4. The solutions were administered intrajejunally through an in-dwelling fistula that was inserted 1 week prior to the octreotide. Intrajejunal administration of 10 mg of octreotide, co-administered with 5 and 10% (w/v) TMC60, resulted in a 7.7-fold and 14.5-fold increase in octreotide absorption with absolute bioavailabilities of 13.9 1.3 and 24.8 1.8%, respectively. The results are presented in Fig. 6.5 (Thanou et al. 2001a). 

Fig. 6.6 Blood plasma profiles of octreotide after peroral administration of 15 mg/pig A, Subject 2 B, Subject 6. Core ( ) core inside ( ) octreotide without any polymer (A) core outside with TMC (x) (Dorkoosh et al. 2002)...

With the advent of new biotechnological techniques endogenous compounds like insulin, buserelin or octreotide have become available at affordable prices. All of these substances still have to undergo needle application. Until today the development of alternative delivery systems for the nasal, buccal, peroral, rectal and pulmonary routes for the administration of those class III drugs according to the biopharmaceutics classification system (BCS) (Amidon et al. 1995) could not keep pace with this development of endogenous compounds or is not economic enough for the health care payers (e.g. insulin application via the pulmonary route). 

A slightly different approach is to deliver the active drug in a dry powder carrier system, for example microcrystalline cellulose, hydroxyethyl starch, cross-linked dextran, microcrystalline chitosan, carbomer, pectin, or alginic acid. The polymer absorbs water upon contact with the nasal mucosa and swells to become a viscous gel, often demonstrating bioadhesive properties. Such systems can remain in the nasal cavity for as long as six hours. For example, the bioavailability in rats of the somatostatin analogue, octreotide, was shown to be enhanced by the co-administration of alginic acid and cross-linked dextran as dry powders. 

OCTREOTIDE ANTICANCER AND IMMUNOMODULATING DRUGS - CICLOSPORIN l plasma concentrations of cidosporin and risk of transplant rejection Octreotide is a strong inducer of CYP3A4-mediated metabolism of cidosporin Avoid co-administration if possible if not, monitor cidosporin levels closely... 

Somatostatin and its synthetic analogue octreotide reduce portal pressure by decreasing splanchnic blood flow. Octreotide has the advantage of a longer duration of action so that it can be given as a bolus injection rather than the constant intravenous infusion needed for administration of somatostatin. Its can be used as an alternative to terlipressin, having similar efficacy and indications for use. 

Somatostatin Somatotropin release inhibiting factor (SRIF) displays antimitotic effects regarding various non-endocrine tumours. In animal experiments, octreotide retards tumour growth. The subcutaneous administration of octreotide (250 gg, 2x/day) resulted in a considerable improvement in survival time and quality of life. (93) There are still no clinical results available regarding the use of lanreotide, which has a longer action time. 

Anti-hormone therapy Gastroenteropancreatic tumours show a good response to the systemic administration of anti-hormonal substances, especially those which are directed against the biological activity and peptide secretion of these tumours. As a result, octreotide ther-... 

Systemic chemotherapy is usually not indicated in non-colorectal liver metastases due to lack of response. The systemic administration of cytostatics (also in combination) possesses the status of palliative therapy. However, in metastatic neuroendocrine tumours, a combination of octreotide -i- IFN had a positive effect on the survival time. Systemic chemotherapy produced remission rates of up to 60%. (320) In metastatic breast cancer, systemic chemotherapy is indicated, usually in combination with hormonal and immune therapy. (316, 342) In metastatic gastric carcinoma, palliative chemotherapy can achieve a remission rate of up to 40%, with a slight extension of survival time. 

Fig. 2 The influence of Sandostatin LAR biodegradable depot formulation on the mean plasma growth hormone concentrations in humans. Plasma concentrations are shown over a 24 hour period 28 days after administration of a second monthly 20mg dose of Sandostatin LAR, . For comparison, plasma concentrations are provided for untreated controls, , and for patients receiving multiple daily subcutaneous octreotide injections, A. (From Refs. ° ° l)...

Recently, Damge et al. showed that the incorporation of octreotide, a somatostatin analogue, in poly(alkylcyanoacrylate) nanocapsules also improved and prolonged the therapeutic effect of this peptide, after administration by the oral route. 

A powerful new synthetic peptide that mimics the action of somatostatin, octreotide acetate (Sandostatin). is approved by the Food and Drug Administration (FDA) for (he treatment of certain rare forms of intestinal endocrine cancers, such as malignant carcinoid tumors and vasoactive intestinal peptide-secreting tumors (VIPomas). Octreotide acetate is indicated for long-term treatment of severe diarrhea associated with these carcinomas. 

Octreotide (Sandostatin) injection is commercially available in the United States for subcutaneous or intravenous administration. A long-acting intramuscular formulation of octreotide (Sandostatin EAR) is also available for monthly administration. In addition to the treatment of acromegaly, octreotide has many other therapeutic uses, including the treatment of carcinoid tumors, vasoactive intestinal peptide tumors (VIPomas), gastrointestinal fistulas, variceal bleeding, diarrheal states, and irritable bowel syndrome. 

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