Multiple once-daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers: a randomized, double-blind, placebo-controlled, cross-over, Phase I study

A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of pasireotide in healthy male subjects. Subjects received pasireotide 50, 200, or 600μgscqd for 14days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection-site reactions (n=18), diarrhea (n=14) and nausea (n=10), which were mostly mild or moderate in intensity. Pasireotide 600μgsc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3days of dosing and PK exposures had a moderate accumulation of 20-40% across doses. Pasireotide demonstrated fast absorption (T max,ss: 0.25-0.5h), low clearance (CL/F ss: 8.10-9.03L/h), long effective half-life (T ½,eff: ~12h, on average between 9.7 and 13.1h for 50, 200, and 600μgscqd), and large volume of distribution (V z/F ss: 251-1,091L) at steady state. Dose proportionality was confirmed for C max,ss; other PK parameters (C max, AUC0-24h and AUCtau) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600μgscqd. Gallbladder volume increased post-prandially with pasireotide 200 and 600μgscqd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600μgqd, with a linear and time-independent PK profile after sc qd dosing in healthy subject

Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: Results from a phase II study

Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst 1,2,3) and sst5. Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150 μg twice daily (bid), escalated to a maximum dose of 1200 μg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600-900 μg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600-900 μg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy