Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, South San Francisco, CA, USA.
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA.
Clin Pharmacokinet. 2022 Jun;61(6):833-845. doi: 10.1007/s40262-021-01094-y. Epub 2022 Mar 2.
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 (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.
Cotadutide 是一种平衡的双重胰高血糖素样肽-1/胰高血糖素受体激动剂，正在开发用于治疗非酒精性脂肪性肝炎和伴有 2 型糖尿病的慢性肾脏病。本分析的目的是描述 2 型糖尿病患者每日皮下注射 cotadutide 的群体药代动力学特征，并评估人口统计学和临床相关变量对 cotadutide 药代动力学的影响。
本研究分析了来自 759 例 2 型糖尿病患者的 8834 个 cotadutide 血浆浓度，这些患者来自 6 项临床研究，接受了 20 至 600μg 的每日皮下剂量。通过模拟方法进一步评估了体重对 cotadutide 暴露的影响。通过预测校正可视化预测检查评估模型性能。
一个具有一级吸收和消除的一室模型很好地描述了 cotadutide 的药代动力学数据。cotadutide 表观清除率、表观分布容积、吸收速率常数和半衰期的平均值分别为 1.04 L/h（个体间变异[IIV]：26.5%）、18.7 L（IIV：28.7%）、0.343 h（IIV：38.6%）和 12.9 h。体重较高、白蛋白较低和丙氨酸氨基转移酶较高与 cotadutide 清除率增加相关，而抗药物抗体滴度增加与 cotadutide 清除率降低相关。这些具有统计学意义的影响被认为没有临床意义，不需要调整剂量。其他测试的基线协变量（年龄、性别、体重指数、糖化血红蛋白、肾功能、糖尿病病程）对 cotadutide 药代动力学的影响没有统计学意义。
cotadutide 的药代动力学通过具有一级吸收和消除的一室线性模型得到了很好的描述。根据最终的群体药代动力学模型模拟，cotadutide 不需要基于体重的给药。该模型将用于评估 cotadutide 在不同适应证中的疗效和安全性的暴露-反应关系，这些适应证正在研究中。
