An open-label dose-escalation study of once-daily and twice-daily pasireotide in healthy volunteers: safety, tolerability, and effects on glucose, insulin, and glucagon levels.
Pasireotide is a multireceptor-targeted somatostatin analogue that has high affinity for 4 of the 5 somatostatin receptor subtypes (sst1,2,3 and sst5) and has therapeutic potential in conditions with tumors of neuroendocrine origin, such as Cushing disease, acromegaly, and neuroendocrine tumors. This phase 1, open-label, dose-escalation study assessed the overall safety and tolerability of once-daily and twice-daily pasireotide and its effects on glucose, insulin, and glucagon levels in healthy volunteers. Eleven cohorts (n = 6 for each) received subcutaneous pasireotide 150, 300, 600, 900, 1200, or 1500 μg once daily, or 150, 300, 450, 600, or 750 μg twice daily, for 8 days. Pasireotide was generally well tolerated at all doses; adverse events were predominantly mild-to-moderate gastrointestinal disorders. All participants experienced fasting and postprandial plasma glucose elevations after all doses of pasireotide; increases in blood glucose level seemed to be dose dependent. Hyperglycemia was associated with a marked suppression of insulin secretion and a mild inhibition of glucagon secretion. In conclusion, pasireotide showed good overall tolerability at doses up to 1500 μg once daily and 750 μg twice daily for 8 days. Both fasting and postprandial hyperglycemia occurred after all doses of pasireotide, which was related to the suppression of insulin secretion.
1IBERICA Clinical Research Center, Eatontown, NJ; 2Novartis Pharma AG, Basel, Switzerland; and 3Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Magdy
M
Shenouda
Mario
M
Maldonado
Yanfeng
Y
Wang
Emmanuel
E
Bouillaud
Michelle
M
Hudson
Dalal
D
Nesheiwat
Ke
K
Hu
D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005934:Glucagon / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D013004:Somatostatin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
D001786:Blood Glucose; D007328:Insulin; D013004:Somatostatin; D005934:Glucagon; C517782:pasireotide