Safety, tolerability, and pharmacokinetics of a single dose of pasireotide long-acting release in healthy volunteers: a single-center Phase I study

Objective: This study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PKs) of different doses of a long-acting release (LAR) formulation of pasireotide in healthy subjects. Design: Single-center, open-label, randomized Phase I study. Methods: Twelve healthy male subjects received a single s.c. dose of pasireotide 300 mu g followed by a washout period of 7 days (or at least 5 days), before receiving an i.m. injection of pasireotide -LAR 40 mg (n=5) or 60 mg (n=7). Assessments included adverse events (AEs), PKs, and glucose, insulin, glucagon, and HbA1c levels. Results: Pasireotide LAR showed an extended-release profile over 1 month with two concentration peaks observed 1 and around 20 days after injection. The area under curve exposure of pasireotide LAR was dose proportional when the dose levels were compared, and the bioavailability of the LAR relative to the s.c. formulation was complete. Administration of pasireotide LAR resulted in an increase in fasting and postprandial glucose levels; however, an attenuation of the hyperglycemic effect was observed after 15 days. The most frequently reported AEs were mild-to-moderate diarrhea, abdominal pain, and flatulence. Only gastrointestinal AEs and injection site reactions were suspected to be drug related. Conclusions: Pasireotide LAR was generally well tolerated with mostly mild AEs at doses up to 60 mg and showed a dose-proportional, extended-release profile in healthy subjects. Based on the favorable results of this study, further clinical development of pasireotide LAR is under way, which will give insight into the PKs, efficacy, and safety of pasireotide LAR in patient populations.