Pharmacokinetic and technical comparison of Sandostatin® LAR® and other formulations of long-acting octreotide

Abstract

BackgroundSandostatin® LAR® (Novartis Pharma AG) is a long-acting repeatable formulation of the somatostatin analogue octreotide, the safety and efficacy of which has been established through 15 years of clinical experience. Recently, other formulations of octreotide using polymer poly(lactic-co-glycolic acid) technology have been developed. This study compares the composition and pharmacokinetic (PK) profile of Sandostatin LAR with three other versions of the depot delivery system (formulations A, B and C, available in selected countries).FindingsSandostatin LAR exhibited a characteristic concentration-time profile with a limited initial release of octreotide ('burst'), an erosion phase from weeks 3-5, and a slowly declining concentration to day 52. The PK profiles of formulations A and B were characterized by a large initial burst during days 0-2, with up to 41% of the overall area under the plasma-concentration time curve achieved. Low and variable octreotide concentrations were observed during the microparticle erosion phase (days 2-62 [day 82 formulation C]) for formulations A, B and C. Sandostatin LAR microparticles are spherical in shape with an average diameter of approximately 50 μm, determined by scanning electron microscopy evaluation. Formulation A had smaller, irregular microparticles, and formulations B and C exhibited a large range of particle diameters (< 20 to > 100 μm). Inductively coupled plasma-optical emission spectroscopy detected a high tin content of 104 mg/kg in formulation B, the presence of which may suggest inadequate purification following polymer synthesis using tin(II)-octoate as catalyst. PK profiles for formulations A, B and C after a single intramuscular injection of 4 mg/kg in male New Zealand rabbits differed markedly from the PK profile of Sandostatin LAR.ConclusionsClear differences were seen between Sandostatin LAR and formulations A, B and C, including variations in microparticle size, shape and impurity content. Considering the significant differences in the octreotide release profile between Sandostatin LAR and the other formulations, the safety and efficacy of the other formulations cannot be inferred from the Sandostatin LAR efficacy and safety profile; each of these other formulations should be assessed accordingly.

Identification and Assessment of Octreotide Acylation in Polyester Microspheres by LC–MS/MS

“…Octreotide is a synthetic octapeptide analogue of somatostatine which is clinically used for the treatment of acromegaly as well as certain endocrine tumors ( 12 ). Octreotide has poor pharmacokinetics (half-life of 100 min in humans) and therefore a sustained formulation based on PLGA microspheres has been developed which is presently used in the clinic ( 13 ). Octreotide has a free N-terminus and a lysine amine group and has therefore been studied in depth regarding acylation reactions that occur in matrices of PLGA and related aliphatic polyesters ( 14 – 20 ).…”

Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial

“…When presenting the data combined with the long-term results reported by Shen et al (17), the result is very similar to the metaanalysis 6-12 months postoperatively, with a trend for increased cure of macroadenomas by pretreatment representing a doubled cure rate in the pretreated group. Particularly octreotide but also lanreotide has been proven to have a long biological half-life when given in slow-release formulas, and can be detected in circulation many weeks after injection (20,21). A phase I study demonstrated that the concentration of octreotide LAR decreases slowly to immeasurable values in the first 11 weeks after a single injection (22).…”

Diagnosis and treatment of hyperinsulinaemic hypoglycaemia and its implications for paediatric endocrinology

“…Octreotide long-acting release (LAR) is formulated with biodegradable microspheres [127]. This formulation provides the advantage of administration every 28 days.…”