Dulaglutide Case Study

Introduction

Dulaglutide is a Glucagon-like peptide-1 (GLP-1) receptor agonist (RA) indicated for the treatment of type 2 diabetes mellitus (T2DM). Dulaglutide was invented by Wolfgang Glaesner, Rohn Lee Millican Jr, and Andrew Mark Vick, employees of Eli Lilly and Company. In the United States dulaglutide is manufactured by Eli Lilly and Company in Indianapolis, Indiana under the trade name Trulicity. T2DM is a progressive disease that is characterized by the dysfunction of β pancreatic islet cells that produce insulin, insulin resistance and hyperglucogonaemia, all which contribute to chronic hyperglycemia (Glaesner, et al., 2010). GLP-1 (or incretin) is a hormone secreted by intestinal endocrine cells following a meal. GLP-1 supports
These purified islets were incubated in a salt solution with 2.8mM to 16.8 mM glucose and increasing levels of dulaglutide with or without exendin, a well characterized GLP-1 receptor agonist (Ding, et al., 2006). Insulin was then measured over a 90-minute period. Insulin secretion was significantly increased with the inclusion of 20 nM dulaglutide at the high dose of glucose (16.8 mM), and no significant increase in insulin secretion was observed in the low dose of glucose (2.8 mM). Unmodified GLP-1 caused a 4-fold increase in insulin secretion, whereas dulaglutide caused a 3-fold increase in insulin secretion, demonstrating that dulaglutide is nearly as efficacious as GLP-1 in stimulating insulin secretion. The EC50 of insulin secretion by dulaglutide was observed at 2.7 nM, while the Emax was observed at 300 nM. The inclusion of exendin reversed the glucose dependent stimulation of insulin secretion that was observed with dulaglutide suggesting that dulaglutide acts on the islet GLP-1 receptor (Glaesner, et al., 2010).

Following results demonstrating increased insulin secretion in the rat islet cells, the test was repeated using pancreatic cells from cynomolgus monkeys. The monkey cells were cultured in RPMI-1640 medium and were starved in EBSS containing 2.8 mM glucose. Batches of three islets were incubated in EBSS and 16.7 mM glucose and increasing levels of dulaglutide with or without exendin. The results from the rat studies
Adult male rats received a single subcutaneous dose of 0.1 mg per kg dulaglutide, and blood samples were collected 1,2,4 and 6 days following administration. A group of 3 monkeys received a subcutaneous dose of 0.1 mg per kg dulaglutide and blood samples were collected at 0, 2, 4, 12, 48, 72 96, 192, 240, 288 and 336 hours following administration. Samples from both animals were studies for GLP-1-Fc concentration using ELISA, utilizing antibodies that recognize the N-terminus of GLP-1-Fc and the Fc domain. Optical density of tetramethylbenzidine development was measured and concentrations of GLP-1-Fc were calculated using the four parameter algorithm (Glaesner, et al., 2010). The pharmacokinetic parameters of dulaglutide for rats and monkeys respectively were: t1/2= 38.2 hours, and 51.6 hours; Cmax = 179.7 ng/mL, and 292.2 ng/mL; Tmax= 24 hours, and 16.7 hours; Cl = 9.6 ml/h/kg, and 7.3 mL/h/kg; VD = 525.0 mL/kg, and 557.5 mL/kg; AUC0- ∞ = 10,537 and 15,207 (Glaesner, et al., 2010; Jimenez-Solem et al.,