Octreotide s.c. depot provides sustained octreotide bioavailability and similar IGF-1 suppression to octreotide LAR in healthy volunteers

Abstract

Aims: The aim was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of octreotide subcutaneous (s.c.) depot, a novel octreotide formulation.

Methods: This was a phase I, randomized, open label study. After a single dose of octreotide immediate release (IR) 200 µg, subjects were randomized to one of eight groups to receive three monthly injections of octreotide s.c. depot A 10, 20 or 30 mg, B 30 mg, C 10, 20 or 30 mg or long acting octreotide (octreotide LAR) 30 mg.

Results: One hundred and twenty-two subjects were randomized. For all depot variants, onset of octreotide release was rapid and sustained for up to 4 weeks. The relative octreotide bioavailability of depot variants vs. octreotide IR ranged from 0.68 (90% confidence interval [CI] 0.61, 0.76) to 0.91 (90% CI 0.81, 1.02) and, vs. octreotide LAR, was approximately four- to five-fold greater: 3.97 (90% CI 3.35, 4.71) to 5.27 ng ml(-1) h (90% CI 4.43, 6.27). All depot variants showed relatively rapid initial reductions of insulin-like growth factor 1 (IGF-1) compared with octreotide LAR. A trend of octreotide dose dependence was also indicated from the plasma concentrations and suppression of IGF-1. Maximum inhibition of IGF-1 at steady-state was highest for depot B and C. All depot treatments were well tolerated. The most frequent adverse events were gastrointestinal related.

Conclusions: Octreotide s.c. depot provides greater octreotide bioavailability with a more rapid onset and stronger suppression of IGF-1 than octreotide LAR in healthy volunteers.

Keywords: FluidCrystal®; depot; formulation; injection; octreotide; subcutaneous.

Figure 1

Mean octreotide plasma concentrations by sampling time (PK population) for A) octreotide IR for each of the randomized arms (octreotide IR (200 μg) for each of the following: , octreotide s.c. depot A, 10 mg; , octreotide s.c. depot A, 20 mg; , octreotide s.c. depot A, 30 mg; , octreotide s.c. depot B, 30 mg; , octreotide s.c. depot C, 10 mg; , octreotide s.c. depot C, 20 mg; , octreotide s.c. depot C, 30 mg; , octreotide LAR, 30 mg), B) octreotide s.c. depot A (, octreotide s.c. depot A, 10 mg; , octreotide s.c. depot A, 20 mg; , octreotide s.c. depot A, 30 mg), C) octreotide s.c. depot B (, octreotide s.c. depot B, 30 mg), D) octreotide s.c. depot C (, octreotide s.c. depot C, 10 mg; , octreotide s.c. depot C, 20 mg; , octreotide s.c. depot C, 30 mg), E) octreotide LAR (, octreotide LAR, 30 mg) and F) octreotide s.c. depot B superimposed with octreotide LAR (, octreotide s.c. depot B, 30 mg; , octreotide LAR, 30 mg)

Figure 2

Inhibition of IGF-1 concentrations (absolute values) by sampling time (EVAL population) for A) octreotide IR for each of the randomized arms (octreotide IR (200 μg) for each of the following: , octreotide s.c. depot A, 10 mg; , octreotide s.c. depot A, 20 mg; , octreotide s.c. depot A, 30 mg; , octreotide s.c. depot B, 30 mg; , octreotide s.c. depot C, 10 mg; , octreotide s.c. depot C, 20 mg; , octreotide s.c. depot C, 30 mg; , octreotide LAR, 30 mg), B) octreotide s.c. depot A (, octreotide s.c. depot A, 10 mg; , octreotide s.c. depot A, 20 mg; , octreotide s.c. depot A, 30 mg), C) octreotide s.c. depot B (, octreotide s.c. depot B, 30 mg), D) octreotide s.c. depot C (, octreotide s.c. depot C, 10 mg; , octreotide s.c. depot C, 20 mg; , octreotide s.c. depot C, 30 mg), E) octreotide LAR (, octreotide LAR, 30 mg) and F) octreotide s.c. depot B superimposed with octreotide LAR (, octreotide s.c. depot B, 30 mg; , octreotide LAR, 30 mg)

Figure 3

Suppression of IGF-1 concentrations (percentage AUC inhibition) for all doses of randomized treatments after the first and third injections. , Oct s.c. depot A, first dose; , Oct s.c. depot B, first dose; , Oct s.c. depot C, first dose; , Oct LAR, first dose; , Oct s.c. depot A, third dose; , Oct s.c. depot B, third dose; , Oct s.c. depot C, third dose; , Oct LAR, third dose