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Population Pharmacokinetics of Cotadutide in Subjects with Type 2 Diabetes

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Background and Objectives

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.

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This study was funded by AstraZeneca. The authors thank Lars Hansen, M.D., Ph.D., (Early Clinical Development, AstraZeneca) for his review and valued medical field support of this work.

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Authors and Affiliations


Corresponding author

Correspondence to Rosalinda H. Arends.

Ethics declarations


This study was funded by AstraZeneca.

Conflict of interest

Rosalinda H. Arends is an employee of AstraZeneca and owns stock in AstraZeneca. Ye Guan, Neang Ly, and Jing Li were employees of AstraZeneca. Neang Ly and Jing Li owned stock in AstraZeneca at the time the study was conducted.

Ethics approval

All studies were conducted in accordance with the principles in the Declaration of Helsinki. Clinical protocols were reviewed and approved for each site by institutional review boards.

Consent to participate

All subjects enrolled provided written informed consent prior to participation in the studies.

Consent for publication

Not applicable.

Code availability

Not applicable.

Availability of data and material

No data have been shared.

Authors’ contributions

YG and JL wrote the manuscript. YG, NL, and JL designed and conducted the pharmacometric analysis. YG, NL, JL, and RA contributed to data acquisition and interpretation. All authors revised the manuscript and accepted its form for submission. This work focuses on population pharmacokinetic modeling using pooled data from six clinical trials, which involves multiple principal investigators across different countries. As the principal investigators of the clinical trials did not participate in the modeling analysis work, they are not included as authors on this paper. However, Lars Hansen, MD, PhD, (Early Clinical Development, AstraZeneca) oversees the clinical aspects for the cotadutide program including the current analysis.

Additional information

Ye Guan, Neang Ly, Jing Li were former employees of AstraZeneca.

Supplementary Information

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Guan, Y., Ly, N., Li, J. et al. Population Pharmacokinetics of Cotadutide in Subjects with Type 2 Diabetes. Clin Pharmacokinet 61, 833–845 (2022).

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