Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Clin Pharmacokinet. 2022 Jul;61(7):1057-1067. doi: 10.1007/s40262-022-01140-3. Epub 2022 Jun 8.
Tirzepatide, a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US as a treatment for type 2 diabetes and is under development for long-term weight management, heart failure with preserved ejection fraction, and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics and tolerability of tirzepatide in participants with hepatic impairment (with or without type 2 diabetes) versus healthy participants with normal hepatic function.
Participants in this parallel, single-dose, open-label study were categorized by hepatic impairment defined by the baseline Child-Pugh (CP) score A (mild impairment; n = 6), B (moderate impairment; n = 6), or C (severe impairment; n = 7) or normal hepatic function (n = 13). All participants received a single subcutaneous 5-mg dose of tirzepatide. Blood samples were collected to determine tirzepatide plasma concentrations to estimate pharmacokinetic parameters. The primary pharmacokinetic parameters of area under the drug concentration-time curve from zero to infinity (AUC) and maximum observed drug concentration (C) were evaluated using an analysis of covariance. The geometric least-squares means (LSM) and mean ratios for each group, between control and hepatic impairment levels, and the corresponding 90% confidence intervals (CIs) were estimated. The analysis of the time to maximum observed drug concentration was based on a nonparametric method. The relationships between the pharmacokinetic parameters and CP classification parameters (serum albumin level, total bilirubin level, and international normalized ratio) were also assessed. Adverse events were monitored to assess safety and tolerability.
Tirzepatide exposure, based on AUC and C, was similar across the control and hepatic impairment groups. Statistical analysis showed no difference in the geometric LSM AUC or C between participants in the control group and the hepatic impairment groups, with the 90% CI for the ratios of geometric LSM spanning unity (AUC ratio of geometric LSM vs control [90% CI 1.08 [0.879, 1.32], 0.960 [0.790, 1.17], and 0.852 [0.699, 1.04] and C ratio of geometric LSM vs control [90% CI]: 0.916 [0.726, 1.16], 1.00 [0.802, 1.25], and 0.972 [0.784, 1.21] for mild, moderate and severe hepatic impairment groups, respectively). There was no change in median time to C of tirzepatide across all groups (time to C median difference vs control [90% CI]: 0 [- 4.00, 12.00], 0 [- 12.00, 12.00], and 0 [- 11.83, 4.17], respectively). There was no significant relationship between the exposure of tirzepatide and the CP score (p > 0.1 for AUC, C, and apparent total body clearance). Similarly, there was no clinically relevant relationship between the exposure of tirzepatide and serum albumin level, total bilirubin level, or international normalized ratio. The geometric LSM half-life values were also similar across the control and hepatic impairment groups. No notable differences in safety profiles were observed between participants with hepatic impairment and healthy control participants.
Tirzepatide pharmacokinetics was similar in participants with varying degrees of hepatic impairment compared with healthy participants. Thus, people with hepatic impairment treated with tirzepatide may not require dose adjustments.
ClinicalTrials.gov identifier number NCT03940742.
Tirzepatide 是一种新型每周一次的双重葡萄糖依赖性胰岛素促分泌多肽和胰高血糖素样肽-1 受体激动剂，已获美国批准用于治疗 2 型糖尿病，并正在开发用于长期体重管理、射血分数保留型心力衰竭和非酒精性脂肪性肝炎。本研究评估了肝损伤（伴或不伴 2 型糖尿病）与肝功能正常的健康参与者相比，tirzepatide 的药代动力学和耐受性。
本平行、单次、开放标签研究根据基线 Child-Pugh（CP）评分 A（轻度损伤；n=6）、B（中度损伤；n=6）或 C（重度损伤；n=7）或正常肝功能（n=13）将参与者分类。所有参与者均接受了一次皮下 5mg 的 tirzepatide 剂量。采集血样以确定 tirzepatide 的血浆浓度，以估算药代动力学参数。使用协方差分析评估药时曲线下面积从 0 到无穷大（AUC）和最大观测药物浓度（C）的主要药代动力学参数。使用每组的几何均数（LSM）和均值比（与对照和肝损伤水平相比）以及相应的 90%置信区间（CI）进行估计。最大观测药物浓度的分析基于非参数方法。还评估了药代动力学参数与 CP 分类参数（血清白蛋白水平、总胆红素水平和国际标准化比值）之间的关系。监测不良事件以评估安全性和耐受性。
在对照和肝损伤组中，tirzepatide 的暴露量（基于 AUC 和 C）相似。统计分析显示，与肝损伤组相比，对照组中参与者的几何均数 AUC 或 C 无差异，比值的 90%CI 跨越 1（AUC 比值的几何均数与对照 [90%CI 1.08 [0.879, 1.32]，0.960 [0.790, 1.17]，0.852 [0.699, 1.04]和 C 比值的几何均数与对照 [90%CI]：0.916 [0.726, 1.16]，1.00 [0.802, 1.25]，0.972 [0.784, 1.21]）。所有组的 tirzepatide 达到 C 的中位数时间无变化（与对照相比的 C 中位数差异时间 [90%CI]：0 [-4.00, 12.00]，0 [-12.00, 12.00]和 0 [-11.83, 4.17]）。tirzepatide 的暴露量与 CP 评分之间没有显著关系（AUC、C 和表观总清除率的 p>0.1）。同样，tirzepatide 的暴露量与血清白蛋白水平、总胆红素水平或国际标准化比值之间也没有临床相关关系。几何均数半衰期值在对照组和肝损伤组之间也相似。在肝损伤患者和健康对照参与者之间未观察到安全性特征的显著差异。
与健康参与者相比，不同程度肝损伤患者的 tirzepatide 药代动力学相似。因此，接受 tirzepatide 治疗的肝损伤患者可能不需要调整剂量。
ClinicalTrials.gov 标识符号 NCT03940742。
