title: Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys.
abstract: Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.
authors.affiliation: 1Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Myer
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Romach
authors.forename: Chandikumar S
authors.initials: CS
authors.lastname: Elangbam
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D000882:Haplorhini; D053612:Janus Kinases / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D013045:Species Specificity
chemical_list: C488719:GI 181771X; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; D058539:Phosphatidylinositol 3-Kinase; C089212:protein kinase D; D053612:Janus Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D008049:Lipase; D000681:Amylases
keywords: acinar cell hypertrophy/atrophy; cholecystokinin 1 receptor; cynomolgus monkey.; focal acinar cell hyperplasia; necrotizing pancreatitis; rodent pancreas; zymogen degranulation