Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Clin Pharmacokinet. 2021 Aug;60(8):1049-1059. doi: 10.1007/s40262-021-01012-2. Epub 2021 Mar 29.
The pharmacokinetics (PK) and single-dose tolerability of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist being developed for once-weekly treatment of type 2 diabetes (T2D), weight management, and nonalcoholic steatohepatitis, was evaluated in subjects with renal impairment versus healthy subjects with normal renal function.
Forty-five subjects, categorized by baseline renal status, i.e. mild (n = 8, estimated glomerular filtration rate [eGFR] 60-89 mL/min/1.73m), moderate (n = 8, eGFR 30-59 mL/min/1.73m), severe renal impairment (n = 7, eGFR < 30 mL/min/1.73m), end-stage renal disease requiring dialysis (n = 8), and normal renal function (n = 14, eGFR ≥ 90 mL/min/1.73m), received a single subcutaneous dose of tirzepatide 5 mg. Tirzepatide plasma concentrations up to 648 h postdose were measured to compute PK parameters. The primary analysis evaluated the ratios of area under the plasma concentration-time curves (AUCs) and maximum plasma drug concentration (C) of renal impairment versus the normal renal function group (90% confidence interval [CI]). In addition, the relationship between PK parameters and continuous variables of renal function was assessed by linear regression.
Tirzepatide exposure was similar across renal impairment groups and healthy subjects. The 90% CI of ratios of AUCs and C comparing each renal impairment group versus normal renal function spanned unity, except for a 25-29% increase in AUCs in the moderate renal impairment group. There was no significant relationship between tirzepatide exposure and eGFR. Few adverse events were reported across the renal impairment and normal renal function groups. The majority were mild in severity and of a gastrointestinal nature in the renal impairment groups.
There were no clinically relevant effects of renal impairment on tirzepatide PK. Dose adjustment may not be required for patients with renal impairment.
ClinicalTrials.gov NCT03482024.
替西帕肽是一种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，正在开发用于每周一次治疗 2 型糖尿病（T2D）、体重管理和非酒精性脂肪性肝炎。本研究评估了肾功能损害受试者与肾功能正常的健康受试者单次给药的药代动力学（PK）和耐受性。
45 名受试者根据基线肾功能分为轻度（n=8，估算肾小球滤过率[eGFR]60-89mL/min/1.73m）、中度（n=8，eGFR 30-59mL/min/1.73m）、重度肾功能损害（n=7，eGFR <30mL/min/1.73m）、终末期肾病需要透析（n=8）和肾功能正常（n=14，eGFR≥90mL/min/1.73m），接受单次皮下注射 5mg 替西帕肽。测量给药后 648 小时内的替西帕肽血药浓度，计算 PK 参数。主要分析评估了肾功能损害组与肾功能正常组的 AUC 和最大血药浓度（C）的比值（90%置信区间[CI]）。此外，通过线性回归评估了 PK 参数与肾功能连续变量的关系。
替西帕肽在肾功能损害组和健康受试者中的暴露情况相似。除中度肾功能损害组 AUC 比值增加 25-29%外，各肾功能损害组与肾功能正常组的 AUC 和 C 比值的 90%CI 均在 1 以内。替西帕肽暴露与 eGFR 之间无显著关系。肾功能损害组和肾功能正常组报告的不良事件较少。大多数为轻度，且以胃肠道性质为主。
肾功能损害对替西帕肽 PK 无临床相关影响。肾功能损害患者可能无需调整剂量。
ClinicalTrials.gov NCT03482024。
