The Effect of Various Degrees of Renal or Hepatic Impairment on the Pharmacokinetic Properties of Once-Weekly Insulin Icodec.

IF 4.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Clinical Pharmacokinetics Pub Date : 2024-06-01 Epub Date: 2024-05-09 DOI:10.1007/s40262-024-01375-2

Hanne Haahr, Blanka Cieslarová, Janne R Hingst, Shan Jiang, Niels R Kristensen, Viera Kupčová, Lea Nørgreen, Frank-Dietrich H Wagner, Stanislav Ignatenko

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Abstract

Background and objective: Icodec is a once-weekly insulin being developed to provide basal insulin coverage in diabetes mellitus. This study evaluated the effects of renal or hepatic impairment on icodec pharmacokinetics.

Methods: Two open-label, parallel-group, single-dose (1.5 U/kg subcutaneously) trials were conducted. In a renal impairment trial, 58 individuals were allocated to normal renal function (measured glomerular filtration rate ≥ 90 mL/min), mild (60 to < 90 mL/min), moderate (30 to < 60 mL/min) or severe (< 30 mL/min) renal impairment or end-stage renal disease. In a hepatic impairment trial, 25 individuals were allocated to normal hepatic function or mild (Child-Pugh Classification grade A), moderate (grade B) or severe (grade C) hepatic impairment. Blood was sampled frequently for a pharmacokinetic analysis until 35 days post-dose.

Results: The shape of the icodec pharmacokinetic profile was not affected by renal or hepatic impairment. Total icodec exposure was greater for mild (estimated ratio [95% confidence interval]: 1.12 [1.01; 1.24]), moderate (1.24 [1.12; 1.37]) and severe (1.28 [1.16; 1.42]) renal impairment, and for end-stage renal disease (1.14 [1.03; 1.28]), compared with normal renal function. It was also greater for mild (1.13 [1.00; 1.28]) and moderate (1.15 [1.02; 1.29]) hepatic impairment versus normal hepatic function. There was no statistically significant difference between severe hepatic impairment and normal hepatic function. Serum albumin levels (range 2.7-5.1 g/dL) did not statistically significantly influence icodec exposure.

Conclusions: The clinical relevance of the slightly higher icodec exposure with renal or hepatic impairment is limited as icodec should be dosed according to individual need. No specific icodec dose adjustment is required in renal or hepatic impairment.

Clinical trial registration: ClinicalTrials.gov identifiers: NCT03723785 and NCT04597697.

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不同程度的肾功能或肝功能损伤对每周一次的伊科达克胰岛素药代动力学特性的影响

背景和目的：Icodec 是一种正在开发的每周一次的胰岛素，用于为糖尿病患者提供基础胰岛素。本研究评估了肝肾功能损害对 icodec 药代动力学的影响：进行了两项开放标签、平行组、单剂量（1.5 U/kg皮下注射）试验。在肾功能损害试验中，58 人被分配到肾功能正常（测定的肾小球滤过率≥ 90 mL/min）、轻度肾功能损害（60 至结果）、中度肾功能损害（60 至结果）和重度肾功能损害（60 至结果）组：icodec药代动力学曲线的形状不受肝肾功能损害的影响。与正常肾功能相比，轻度（估计比值比[95% 置信区间]：1.12 [1.01; 1.24]）、中度（1.24 [1.12; 1.37]）和重度（1.28 [1.16; 1.42]）肾功能损害以及终末期肾病（1.14 [1.03; 1.28]）患者的 icodec 总暴露量更大。肝功能轻度受损（1.13 [1.00; 1.28]）和中度受损（1.15 [1.02; 1.29]）与肝功能正常相比，差异也较大。严重肝功能损害与正常肝功能之间的差异无统计学意义。血清白蛋白水平（范围为 2.7-5.1 g/dL）对 icodec 暴露的影响无统计学意义：结论：肾功能或肝功能受损时，icodec 暴露略高的临床意义有限，因为icodec 的剂量应根据个人需要而定。肾功能或肝功能受损者无需调整icodec的具体剂量：临床试验注册：ClinicalTrials.gov identifiers：临床试验注册：ClinicalTrials.gov标识符：NCT03723785和NCT04597697。

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来源期刊

Clinical Pharmacokinetics 医学-药学

CiteScore

8.80

自引率

4.40%

发文量

审稿时长

6-12 weeks

期刊介绍： Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.