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Population Pharmacokinetic Modeling of Cotadutide: A Dual Agonist Peptide of Glucagon-Like Peptide and Glucagon Receptors Administered to Participants with Type II Diabetes Mellitus, Chronic Kidney Disease, Obesity and Non-Alcoholic Steatohepatitis

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Abstract

Background

Cotadutide is a dual glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor agonist peptide. The objective of this analysis was to develop a population pharmacokinetic (popPK) model of cotadutide, and to identify any potential effect on the PK from intrinsic and extrinsic covariates.

Methods

The popPK analysis utilized a non-linear mixed-effects modeling approach using the data from 10 clinical studies in different participant categories following once-daily subcutaneous dose administration ranging from 20 to 600 μg. Additionally, the covariates affecting cotadutide exposure were quantified, and the model performance was evaluated through the prediction-corrected visual predictive checks.

Results

A one-compartment model with first-order absorption and elimination adequately described the data as confirmed via visual predictive check plots and parameter plausibility. The mean values for cotadutide apparent clearance (CL/F), apparent volume of distribution (V/F), absorption rate constant (Ka), and half-life were 1.05 L/h, 20.0 L, 0.38 h–1, and 13.3 hours, respectively. Covariate modeling identified body weight, alanine transaminase, albumin, anti-drug antibody (ADA) titer values, formulation strength and injection device, and participant categories as significant covariates on PK parameters, where ADAs have been identified to decrease cotadutide clearance. The model demonstrated that a 150-kg participant was estimated to have 30% lower for both AUC and Cmax and a 66 kg participant was estimated to have 35% higher for both AUC and Cmax relative to a reference individual with a median weight of 96 kg.

Conclusions

A popPK model was developed for cotadutide with cotadutide clinical data, and the impact of the statistically significant covariates identified was not considered clinically meaningful. The popPK model will be used to evaluate exposure–response relationships for cotadutide clinical data.

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Acknowledgement

This study was funded by AstraZeneca PLC. The authors would like to thank Dinko Rekić, Ph.D. (Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca), Sebastian Ueckert, Ph.D. (Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca), Robert J. Kubiak, Ph.D. (Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca), Lars Hansen, M.D., Ph.D., (Early Clinical Development, AstraZeneca), Darren Robertson Ph.D. (Early Clinical Development, AstraZeneca), and Sudha S. Shankar M.D. (Early Clinical Development, AstraZeneca) for their review and valued technical/medical field support of this work.

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Correspondence to Hongtao Yu.

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Funding

This study was funded by AstraZeneca.

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All authors are employees of AstraZeneca and own stocks or stock options in AstraZeneca.

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Data Availability Statement

Data underlying the findings described in this paper may be obtained in accordance with AstraZeneca’s data sharing policy described at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Author Contributions

Hongtao Yu collected the data and implemented the popPK model. Hongtao Yu, Magnus Åstrand, and Nitin Kaila interpreted the data. Hongtao Yu drafted the paper. All authors were involved in critical revisions of the paper for important intellectual content and in the approval of the final version.

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Yu, H., Åstrand, M., Cheng, J. et al. Population Pharmacokinetic Modeling of Cotadutide: A Dual Agonist Peptide of Glucagon-Like Peptide and Glucagon Receptors Administered to Participants with Type II Diabetes Mellitus, Chronic Kidney Disease, Obesity and Non-Alcoholic Steatohepatitis. Clin Pharmacokinet 63, 255–267 (2024). https://doi.org/10.1007/s40262-023-01337-0

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