A Combined Modeling Approach to Predict the Effect of Gastric Emptying Delay on the Pharmacokinetics of Small Molecules.

Abstract

Dulaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, is approved for improving glycemic control and reducing cardiovascular risks in patients with type 2 diabetes mellitus (T2DM). This research investigates the effect of dulaglutide on gastric emptying and its impact on the pharmacokinetics (PK) of orally administered molecules utilizing a combination of population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) modeling approaches. In clinical studies, the gastric emptying delay (GED) was evaluated in healthy participants and patients with T2DM at various dose levels of dulaglutide. A PopPK model estimated the exposure-dependent delay in gastric emptying, which was then input into the orally administered small molecule PBPK models. These PBPK models, informed by internal clinical studies and publicly available data, quantified the effect of dulaglutide-induced GED on the area under the curve (AUC), maximum concentration (C_max), and time to maximum concentration (t_max) of the co-administered drugs. The modeling approach was verified for reproducing observed GED-mediated drug-drug interactions (DDIs) at low doses of dulaglutide and to predict DDIs at a 4.5 mg dulaglutide dose. The clinical studies demonstrated that the 1.5 mg dulaglutide dose has no clinically relevant effect on the pharmacokinetics of small molecules, and the modeling led to a similar conclusion at 4.5 mg dulaglutide. This work demonstrates that modeling approaches can be used to predict potential GLP-1-mediated DDIs related to gastric emptying delay, increasing the efficiency of the clinical pharmacology programs.