title: Safety, tolerability, pharmacokinetics, and pharmacodynamics of a long-acting release (LAR) formulation of pasireotide (SOM230) in patients with gastroenteropancreatic neuroendocrine tumors: results from a randomized, multicenter, open-label, phase I study.
abstract: OBJECTIVE
  Pasireotide (SOM230), a novel multireceptor ligand somatostatin analog (SSA), binds with high affinity to four of the five somatostatin receptor subtypes (sst1-3, 5). This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics profiles of pasireotide long-acting release (LAR) formulation in patients with advanced gastroenteropancreatic neuroendocrine tumor (GEP NET) refractory to other SSAs.
  
  
  METHODS
  In this randomized, multicenter, open-label, phase II study, patients with biopsy-proven primary or metastatic GEP NET refractory to available SSAs were randomly assigned 1:1:1 to receive pasireotide LAR by deep intragluteal injection at a dose of 20, 40, or 60 mg once every 28 days for 3 months.
  
  
  RESULTS
  Forty-two patients received pasireotide LAR. Adverse events were reported by 34 (81 %) patients, with the most frequently reported including diarrhea, fatigue, abdominal pain, and nausea. Mean fasting glucose levels were increased compared with baseline at all points throughout the study. After the third injection of pasireotide LAR, the median trough plasma concentrations on day 84 were 4.82, 12.0, and 19.7 ng/mL in the 20-, 40-, and 60-mg treatment groups, respectively. Drug accumulation was limited for each dose based on the increase in trough concentrations after the first to third injections (accumulation ratios were approximately 1 from all dose levels).
  
  
  CONCLUSIONS
  This study demonstrated that a new, once-monthly, intramuscular LAR formulation of pasireotide was well tolerated in patients with advanced GEP NET. Steady state levels of plasma pasireotide were achieved after three injections.
authors.affiliation: Carcinoid/Neuroendocrine Tumor Program, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. edward.wolin@cshs.org
authors.forename: Edward M
authors.initials: EM
authors.lastname: Wolin
authors.forename: Ke
authors.initials: K
authors.lastname: Hu
authors.forename: Gareth
authors.initials: G
authors.lastname: Hughes
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bouillaud
authors.forename: Vanessa
authors.initials: V
authors.lastname: Giannone
authors.forename: Karina Hermosillo
authors.initials: KH
authors.lastname: Resendiz
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D003672:Defecation / Q000187:drug effects; D003692:Delayed-Action Preparations; D003967:Diarrhea / Q000150:complications; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D008297:Male; D008303:Malignant Carcinoid Syndrome / Q000150:complications; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000378:metabolism*; D013004:Somatostatin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D013004:Somatostatin; C517782:pasireotide