Population Pharmacokinetics of Cotadutide in Subjects with Type 2 Diabetes

Cotadutide is a balanced dual glucagon-like peptide-1/glucagon receptor agonist under development for the treatment of nonalcoholic steatohepatitis and chronic kidney disease with type 2 diabetes. The objectives of the analysis were to characterize the population pharmacokinetics of cotadutide following daily subcutaneous injection in subjects with type 2 diabetes and to evaluate the effect of demographic and clinical variables of interest on cotadutide pharmacokinetics.

This study analyzed 8834 plasma concentrations of cotadutide from 759 subjects with type 2 diabetes who received daily subcutaneous doses from 20 to 600 μg from six clinical studies. The impact of covariates on cotadutide pharmacokinetics was quantified, and body weight effect on cotadutide exposure was further evaluated using a simulation approach. The model performance was evaluated through prediction-corrected visual predictive checks.

A one-compartment model with first-order absorption and elimination described cotadutide pharmacokinetic data well. The mean values for cotadutide apparent clearance, apparent distribution volume, absorption rate constant, and half-life were 1.04 L/h (interindividual variability [IIV]: 26.5%), 18.7 L (IIV: 28.7%), 0.343 h^-1 (IIV: 38.6%), and 12.9 h, respectively. Higher body weight, lower albumin, and higher alanine aminotransferase were associated with an increase in cotadutide clearance, while an increase in anti-drug antibody titers was associated with a decrease in cotadutide clearance. These statistically significant effects were not considered clinically significant and did not warrant dose adjustment. Effects of other tested baseline covariates (age, sex, body mass index, hemoglobin A1c, renal function, duration of diabetes) were not found to statistically significantly affect cotadutide pharmacokinetics.

Cotadutide pharmacokinetics was adequately described by a one-compartment linear model with first-order absorption and elimination. Body weight-based dosing is not necessary for cotadutide based on the simulation using the final population pharmacokinetic modeling. This model will be used to evaluate exposure-response relationships for efficacy and safety in different indications that are being studied for cotadutide.