Endocrine Abstracts

Background: Pasireotide is available in twice-daily subcutaneous (sc) and long-acting intramuscular (im) formulations. Pasireotide sc depot is an investigational extended-release sc formulation designed for improved handling and administration. Results are reported from a Phase I dose-escalating study.

Methods: All subjects received a single dose of pasireotide sc (600 μg) and were randomized 12:2:2 to pasireotide sc depot as a single upper-thigh injection (in five ascending-dose groups: 5, 10, 20 [another group of 12 subjects added at this dose level received a single buttock injection], 40, and 80 mg), long-acting pasireotide (60 mg), or pasireotide s.c. (900 μg) twice daily for 7 days.

Results: 94 subjects (59 male, 35 female) were randomized; 90 (95.7%) completed the study. After pasireotide sc depot injection, pasireotide plasma profiles for all tested doses (5–80 mg) showed a relatively rapid initial release (median t_max 24–97 hours) followed by a slow decay with a half-life suitable for once-monthly dosing. Across the pasireotide sc depot dose range, AUC_inf increased dose proportionally and C_max slightly more than dose proportionally. AUC_inf and C_max for the 40 and 80 mg doses of pasireotide sc depot were within the exposure range for pasireotide im. Pasireotide pharmacokinetic parameters were comparable after buttock and upper-thigh injections of pasireotide sc depot (20 mg). The relative pasireotide bioavailability for pasireotide sc depot versus pasireotide im (60 mg) was 52–98% for the 5–40 mg doses, and 115% for the 80 mg dose. Mean values for maximum relative inhibition of insulin-like growth factor 1 versus baseline were similar for pasireotide sc depot 40 and 80 mg and pasireotide im 60 mg, but slightly lower for pasireotide sc depot 5, 10, and 20 mg. Overall, 76/94 (80.9%) subjects experienced adverse events (AEs). The incidence of AEs was 50%, 83.3%, 91.7%, 50%, 100%, and 100% for subjects in the 5, 10, 20 (upper thigh), 20 (buttock), 40, and 80 mg pasireotide sc depot dose groups, respectively, 100% for pasireotide sc, and 80% for pasireotide im. Diarrhoea (25/94 [26.6%]), injection-site pain (27/94 [28.7%]), and injection-site induration (21/94 [22.3%]) were the most commonly reported AEs. Most AEs were mild to moderate in intensity, with seven grade 3 AEs in five subjects (increased alanine aminotransferase [n=3], diarrhoea [n=2], increased gamma-glutamyl transferase [n=1], and vomiting [n=1]). There were no serious AEs, deaths, or AEs leading to discontinuation.

Conclusions: Pasireotide sc depot provides dose-proportional long-acting release of pasireotide with a safety and tolerability profile comparable to currently available long-acting im and sc formulations.