Pharmacokinetics and Safety of Cotadutide, a GLP-1 and Glucagon Receptor Dual Agonist, in Individuals with Renal Impairment: A Single-Dose, Phase I, Bridging Study

May 4, 2023Clinical pharmacokinetics

How Cotadutide, a Drug Acting on Blood Sugar and Metabolism Receptors, Is Processed and Tolerated in People with Kidney Problems

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Abstract

A total of 37 individuals were enrolled in the study, with AUC and C values for cotadutide being similar across all renal function groups.

For severe renal impairment compared to normal renal function, the AUC geometric mean ratio was 0.99, indicating similar exposure levels.
The lower moderate renal impairment group had an AUC geometric mean ratio of 1.01 relative to normal renal function, suggesting comparable pharmacokinetics.
The upper moderate renal impairment group showed an AUC geometric mean ratio of 1.09 compared to normal renal function.
Treatment-emergent adverse events occurred in 42.9% to 72.7% of participants across all renal function groups, with most being mild to moderate.
Only one participant experienced a severe adverse event during the study, and no positive antidrug antibody results were observed.

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BACKGROUND AND OBJECTIVE: Cotadutide is a balanced glucagon-like peptide-1 and glucagon receptor dual agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes with chronic kidney disease. We evaluated the pharmacokinetics (PK), safety and immunogenicity of a single dose of cotadutide in individuals with varying degrees of renal impairment.

METHODS: In this phase I bridging study, individuals 18-85 years of age, with a body mass index of 17-40 kg/mand varying degrees of renal function {end-stage renal disease (ESRD; creatinine clearance [CrCl] < 20 mL/min); severe renal impairment (CrCl ≥ 20 to < 30 mL/min); lower moderate renal impairment (CrCl ≥ 30 to < 44 mL/min); upper moderate renal impairment (CrCl ≥ 45 to < 60 mL/min); normal renal function (CrCl ≥ 90 mL/min)} were treated with a single dose of subcutaneous cotadutide 100 µg under fasted conditions in the lower abdomen. The co-primary endpoints were area under the plasma concentration-time curve from time zero to 48 h (AUC) and the maximum observed plasma concentration (C) for cotadutide. Safety and immunogenicity were secondary endpoints. This trial is registered with ClinicalTrials.gov (NCT03235375). 2 48max

RESULTS: A total of 37 individuals were enrolled in the study (only three enrolled in the ESRD group, therefore this group was excluded from the primary PK analysis). AUCand Cvalues for cotadutide were similar across all renal function groups {severe renal impairment vs. normal renal function: AUCgeometric mean ratio (GMR) 0.99 (90% confidence interval [CI] 0.76-1.29); lower moderate renal impairment versus normal renal function: AUCGMR 1.01 (90% CI 0.79-1.30); upper moderate renal impairment versus normal renal function: AUCGMR 1.09 (90% CI 0.82-1.43)}. A sensitivity analysis that combined the ESRD and severe renal impairment groups did not show notable changes in the AUCand CGMRs. The incidences of treatment-emergent adverse events (TEAE) ranged from 42.9 to 72.7% across all groups and were mostly mild to moderate in severity. Only one patient had a grade III or worse TEAE during the study period. No positive antidrug antibody results were observed. 48max48 48 48 48max

CONCLUSIONS: These results suggest that the PK and tolerability of cotadutide are unaffected by renal function and that dose adjustments may not be required in individuals with renal impairment.

Key numbers

0.99

AUC Geometric Mean Ratio for Severe Renal Impairment

Comparison of AUC between severe renal impairment and normal renal function.

42.9 to 72.7%

Incidence of Any Treatment-Emergent Adverse Events

Percentage of participants experiencing TEAEs across renal function groups.

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Pharmacokinetics and Safety of Cotadutide, a GLP-1 and Glucagon Receptor Dual Agonist, in Individuals with Renal Impairment: A Single-Dose, Phase I, Bridging Study

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