title: Evaluation of Pepsinogen I as a Biomarker of Drug-induced Gastric Mucosal Injury in Cynomolgus Monkeys.
abstract: Gastric mucosal injury is frequently observed in nonclinical studies of nonhuman primates. Because microscopic evaluation of stomach is generally a terminal procedure, our objective was to determine whether serum pepsinogen I (PG I) could serve as a noninvasive biomarker for detection of gastric mucosal injury in monkey. Serum PG I was measured using a commercial human immunoassay in cynomolgus monkeys ( n = 166) prior to dosing and/or terminally in 11 studies of up to 1 month duration. Mean ( SD) PG I values (ug/L) for monkeys with ( n = 59) and without ( n = 100) gastric mucosal degeneration were 101 (215) and 28 (12.6), respectively. For monkeys with baseline and terminal PG I data, mean ( SD) fold change (ratio of terminal to baseline PG I) for monkeys with ( n = 57) and without ( n = 76) glandular degeneration were 4.1 (11.3) and 1 (0.28). Receiver operating characteristic area under the curve (AUC) data demonstrated moderate diagnostic accuracy for serum PG I for glandular degeneration, AUC ( SE) 0.789 (0.04), with improved diagnostic accuracy as a fold change of baseline, AUC ( SE) 0.816 (0.04), consistent with the large interindividual but low intraindividual variability of serum PG I values in control monkeys. These data demonstrate that serum PG I is a useful biomarker of drug-induced gastric mucosal injury in the cynomolgus monkey.
authors.affiliation: 1 GlaxoSmithKline, Safety Assessment, King of Prussia, Pennsylvania, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ennulat
authors.affiliation: 1 GlaxoSmithKline, Safety Assessment, King of Prussia, Pennsylvania, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lynch
authors.affiliation: 2 GlaxoSmithKline, Statistical Sciences, Research Triangle Park, North Carolina, USA.|3 PAREXEL International, Durham, North Carolina, USA.
authors.forename: Carie L
authors.initials: CL
authors.lastname: Kimbrough
authors.affiliation: 1 GlaxoSmithKline, Safety Assessment, King of Prussia, Pennsylvania, USA.
authors.forename: Rosanna C
authors.initials: RC
authors.lastname: Mirabile
authors.affiliation: 1 GlaxoSmithKline, Safety Assessment, King of Prussia, Pennsylvania, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rehm
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D004353:Drug Evaluation, Preclinical / Q000592:standards* / Q000662:veterinary; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000293:injuries*; D008252:Macaca fascicularis; D008297:Male; D020116:Pepsinogen A / Q000097:blood*; D012189:Retrospective Studies; D018675:Toxicity Tests / Q000592:standards* / Q000662:veterinary
chemical_list: D015415:Biomarkers; D020116:Pepsinogen A
keywords: biomarker; monkey; pepsinogen I; stomach