Population Pharmacokinetics of Cotadutide in Subjects with Type 2 Diabetes

Guan, Yihui; Ly, Neang S.; Li, Jing; Arends, Rosalinda H

doi:10.1007/s40262-021-01094-y

Cited by 10 publications

(6 citation statements)

References 27 publications

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“…These data also support results from a pooled population PK analysis that included patients from an ongoing phase IIb study (NCT04515849), in which non-linear mixed-effects modeling demonstrated consistent absorption and elimination of cotadutide in patients with T2D and three renal function statuses (normal renal function, mild renal impairment, and moderate renal impairment). Renal function was also confirmed as a non-statistically significant baseline covariate on clearance in subjects with T2D [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

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

Klein¹,

Petrone

Yang

et al. 2023

Clin Pharmacokinet

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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/m 2 and 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 48 ) and the maximum observed plasma concentration ( C max ) for cotadutide. Safety and immunogenicity were secondary endpoints. This trial is registered with ClinicalTrials.gov (NCT03235375). 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). AUC 48 and C max values for cotadutide were similar across all renal function groups {severe renal impairment vs. normal renal function: AUC 48 geometric mean ratio (GMR) 0.99 (90% confidence interval [CI] 0.76–1.29); lower moderate renal impairment versus normal renal function: AUC 48 GMR 1.01 (90% CI 0.79–1.30); upper moderate renal impairment versus normal renal function: AUC 48 GMR 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 AUC 48 and C max GMRs. 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. 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. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01239-1.

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Section: Discussionmentioning

confidence: 99%

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

Klein¹,

Petrone

Yang

et al. 2023

Clin Pharmacokinet

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“…The cotadutide pharmacokinetics (PK) were described with a previously published one‐compartment linear PK model with first‐order absorption and elimination (Guan et al, 2022). The individual empirical Bayes parameter estimates (EBEs) of clearance (CL), central volume of distribution (VC) and absorption rate constant (KA) were used to derive individual PK time‐profiles as input for sequential exposure‐response modelling.…”

Section: Methodsmentioning

confidence: 99%

“…The cotadutide pharmacokinetics (PK) were described with a previously published one-compartment linear PK model with first-order absorption and elimination (Guan et al, 2022). The in vivo EC 50 s for endogenous GLP-1 and glucagon were fixed to values estimated with the original 4GI model (Bosch et al, 2022).…”

Section: Modelmentioning

confidence: 99%

“…The effects of cotadutide on fasting biomarker levels and postprandial biomarker excursions were adequately described by the previously developed literature-based 4GI model after fitting. The 4GI model was combined with the cotadutide PK model (Guan et al, 2022), and in vitro potency and free fraction information were used to predict in vivo effects. Individual PK EBEs and the individually observed glucose baseline values were used as input.…”

Section: Model Fittingmentioning

confidence: 99%

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Characterisation of cotadutide's dual GLP‐1/glucagon receptor agonistic effects on glycaemic control using an in vivo human glucose regulation quantitative systems pharmacology model

Bosch,

Petrone,

Arends

et al. 2024

British J Pharmacology

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Background and PurposeCotadutide is a dual GLP‐1 and glucagon receptor agonist with balanced agonistic activity at each receptor designed to harness the advantages on promoting liver health, weight loss and glycaemic control. We characterised the effects of cotadutide on glucose, insulin, GLP‐1, GIP, and glucagon over time in a quantitative manner using our glucose dynamics systems model (4GI systems model), in combination with clinical data from a multiple ascending dose/Phase 2a (MAD/Ph2a) study in overweight and obese subjects with a history of Type 2 diabetes mellitus (NCT02548585).Experimental ApproachThe cotadutide PK‐4GI systems model was calibrated to clinical data by re‐estimating only food related parameters. In vivo cotadutide efficacy was scaled based on in vitro potency. The model was used to explore the effect of weight loss on insulin sensitivity and predict the relative contribution of the GLP‐1 and glucagon receptor agonistic effects on glucose.Key ResultsCotadutide MAD/Ph2a clinical endpoints were successfully predicted. The 4GI model captured a positive effect of weight loss on insulin sensitivity and showed that the stimulating effect of glucagon on glucose production counteracts the GLP‐1 receptor‐mediated decrease in glucose, resulting in a plateau for glucose decrease around a 200‐μg cotadutide dose.Conclusion and ImplicationsThe 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP‐1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds.

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“…The reported plasma halflives of liraglutide and semaglutide are 11-15 h and 1 week, respectively (plasma half-life of GLP-1: 1.5 -5 min) [141][142][143]. The GLP-1R/GCGR dual agonist, cotadutide, is also made up of a palmitoylated 31-mer peptide, and the its plasma half-life in T2DM patients was 12.9 h [144].…”

Section: Exploiting Neonatal Fc Receptor (Fcrn)-mediated Recyclingmentioning

confidence: 99%

Pharmaceutical Strategies to Make Better Drugs for Nonalcoholic Fatty Liver Disease Therapy

Amatya¹,

Lee²,

Min³

et al. 2023

Preprint

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Nonalcoholic fatty liver disease (NAFLD) has become globally prevalent and is the leading cause of chronic liver disease. Although NAFLD is reversible in the early stage without medical intervention, the condition could be sequentially worsened to nonalcoholic steatohepatitis (NASH) and, in the end, cirrhosis and hepatic cancer. The progression of NAFLD is related to various factors such as genetics, pre-disposed metabolic disorders, and immunologic factors. Because of the complexity of the disease, the treatment options are very limited, and, unfortunately, there is yet no clinically available drug. Thankfully, to date, there have been accumulating research efforts and, as a result, different classes of potent drug candidates have been discovered. Besides, there have also been various attempts to explore pharmaceutical strategies to make the drug candidates to be better drugs. In this review, we provided a brief overview of the drug candidates that have undergone clinical trials. In the latter part, the strategies for developing better drugs are discussed.

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Population Pharmacokinetics of Cotadutide in Subjects with Type 2 Diabetes

Cited by 10 publications

References 27 publications

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

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

Characterisation of cotadutide's dual GLP‐1/glucagon receptor agonistic effects on glycaemic control using an in vivo human glucose regulation quantitative systems pharmacology model

Pharmaceutical Strategies to Make Better Drugs for Nonalcoholic Fatty Liver Disease Therapy

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