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Abstract: 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 600 μg sc qd for 14 days 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 600 μg sc 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 3 days of dosing and PK exposures had a moderate accumulation of 20–40 % across doses. Pasireotide demonstrated fast absorption (T max,ss: 0.25–0.5 h), low clearance (CL/F ss: 8.10–9.03 L/h), long effective half-life (T ½,eff: ~12 h, on average between 9.7 and 13.1 h for 50, 200, and 600 μg sc qd), and large volume of distribution (V z/F ss: 251–1,091 L) at steady state. Dose proportionality was confirmed for C max,ss; other PK parameters (C max, AUC0–24 h and AUCtau) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600 μg sc qd. Gallbladder volume increased post-prandially with pasireotide 200 and 600 μg sc qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600 μg qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects.