Esperion Therapeutics, Inc., Ann Arbor, Michigan, USA.
Nucleus Network, Pty., Ltd., Melbourne, Victoria, Australia.
Clin Transl Sci. 2022 Mar;15(3):789-798. doi: 10.1111/cts.13202. Epub 2021 Dec 1.
Bempedoic acid is an ATP citrate lyase inhibitor approved for the treatment of hypercholesterolemia. The objective of this phase I study was to assess the pharmacokinetics (PKs) and safety of bempedoic acid in 24 subjects with normal renal function or mild, moderate, or severe renal impairment. All subjects received a single oral bempedoic acid 180-mg dose and PK parameters were monitored for up to 23 days. Resulting estimates of area under the concentration-time curve exposure following bempedoic acid treatment were 1.5-fold, 2.2-fold, and 2.2-fold higher in subjects with mild, moderate, or severe renal impairment, respectively, compared with subjects with normal renal function. With decreases in renal function, plasma free fraction was increased up to 20.1%, whereas total and unbound clearances were decreased by 55.2% and 62.6%, respectively, in subjects with severe renal impairment relative to those with normal renal function. These observed decreases in total and unbound oral clearance in subjects with decreased renal function are not explained by the increases in free fraction and might therefore also be attributable to changes in bioavailability or intrinsic clearance. Bempedoic acid was generally well-tolerated and the incidence and type of adverse events were not affected by the degree of renal impairment. In conclusion, bempedoic acid exposures in subjects with renal impairment were increased up to approximately two-fold with no safety signals identified, consistent with findings in phase III patients with mild or moderate renal impairment. No dose adjustments are necessary for patients with mild or moderate renal impairment.
贝匹地酸是一种 ATP 柠檬酸裂解酶抑制剂，用于治疗高胆固醇血症。这项 I 期研究的目的是评估 24 例肾功能正常或轻度、中度或重度肾功能损害患者单次口服 180mg 贝匹地酸的药代动力学（PK）和安全性。所有患者均接受单次口服贝匹地酸 180mg 剂量，监测 PK 参数长达 23 天。与肾功能正常的患者相比，轻度、中度和重度肾功能损害的患者贝匹地酸治疗后的 AUC 暴露分别增加了 1.5 倍、2.2 倍和 2.2 倍。随着肾功能的下降，血浆游离分数增加了高达 20.1%，而严重肾功能损害患者的总清除率和未结合清除率分别下降了 55.2%和 62.6%，与肾功能正常的患者相比。这些在肾功能下降的患者中观察到的总清除率和未结合清除率的下降不能用游离分数的增加来解释，因此也可能归因于生物利用度或内在清除率的变化。贝匹地酸总体上耐受性良好，不良反应的发生率和类型不受肾功能损害程度的影响。总之，肾功能损害患者的贝匹地酸暴露增加了约 2 倍，未发现安全信号，与轻度或中度肾功能损害的 III 期患者的研究结果一致。对于轻度或中度肾功能损害的患者，无需调整剂量。
