Tolerability and dose proportional pharmacokinetics of pasireotide administered as a single dose or two divided doses in healthy male volunteers: a single-center, open-label, ascending-dose study.

Pasireotide is a multireceptor-targeted somatostatin analogue with high binding affinity for somatostatin receptor subtypes SST 1, 2, 3, and 5.To evaluate the safety profile, tolerability, and pharmacokinetic profile of pasireotide in single- and divided-dose regimens in healthy volunteers.A single-center, open-label, ascending-dose study was performed in healthy volunteers. Pasireotide, 900, 1200, and 1500 μg SC, was administered as either a single dose or as two divided doses given 12 hours apart, with a 7-day washout period between treatments.Seventeen men (median age, 26 years) were enrolled. Their median weight was 81 kg, and 65% were white. One participant dropped out because of a grade 2 adverse event; most other adverse events were mild and affected the gastrointestinal tract. Blood glucose concentration increased after pasireotide administration, but returned to normal within 10 hours. After single-dose administration, pasireotide plasma concentration peaked rapidly at 15 minutes to 1 hour after dosing, followed by a tri-exponential (α, β, and γ phases) decline over time. Mean t(½) values during the α, β, and γ phases were approximately 2 to 3, 12 to 17, and 54 to 97 hours, respectively. In the single-dose cohort, the mean (SD) AUC(∞) was 110 (29), 149 (42), and 188 (52) h · ng/mL in the 900-, 1200-, and 1500-μg groups, respectively. Time to reach C(max) was 0.69 (0.41), 0.59 (0.38), and 0.56 (0.18) hours in the 900-, 1200-, and 1500-μg groups, respectively. AUC(∞) values were similar in the single-dose and divided-dose cohorts. Mean total body clearance was 8 to 9 L/h across the dosage groups and dosing regimens, indicating a linear pharmacokinetic profile between doses.When administered as a single- or divided-dose regimen, pasireotide had a favorable tolerability profile in this selected group of healthy male volunteers. Its pharmacokinetic profile indicated rapid absorption, low clearance, high volume of distribution, and a long terminal half-life.