扎斯塔普拉赞（一种新型钾竞争性酸阻滞剂）与阿托伐他汀在健康受试者中的稳态药代动力学药物相互作用研究。
完整摘要 · 中文译文
目的：Zastaprazan 是一种新型钾竞争性酸阻滞剂，其代谢经 CYP3A 介导，而阿托伐他汀经 CYP3A4 和转运体介导处置。由于这两种药物可能联合使用，且其净相互作用不能仅从共同的代谢途径推断，本研究评估了它们在稳态下的药代动力学药物相互作用。 参与者与方法：这项开放标签、固定序列、三周期、多次给药的试验纳入了健康的韩国男性受试者。受试者在稳态条件下，分别连续5天接受阿托伐他汀 40 mg 每日一次、zastaprazan 20 mg 每日一次，以及阿托伐他汀与 zastaprazan 联合用药。测量了 zastaprazan、阿托伐他汀和 2-羟基阿托伐他汀的血浆浓度，并计算了 Cmax,ss 和 AUCτ,ss 的几何平均比值（GMR）及其 90% 置信区间（CI）。 结果：24 名健康韩国男性受试者至少接受了一次研究药物给药，其中 22 人被纳入药代动力学分析。阿托伐他汀使 zastaprazan 的 Cmax,ss 降低约 26%（GMR，0.740；90% CI，0.655–0.836），而 AUCτ,ss 保持不变（GMR，1.054；90% CI，0.927–1.198）。Zastaprazan 未明显改变阿托伐他汀的暴露量（Cmax,ss GMR，0.982；90% CI，0.806–1.195；AUCτ,ss GMR，1.029；90% CI，0.944–1.122）。2-羟基阿托伐他汀的 AUCτ,ss 略有下降（GMR，0.940；90% CI，0.889–0.994），但仍保持在预设的常规参考范围内。联合用药总体耐受性良好，未发生严重不良事件或不良…… 因不良事件而停药。 结论：在研究的条件下，扎斯塔普赞未显著改变阿托伐他汀的稳态峰浓度（C max,ss）或稳态给药间隔内药时曲线下面积（AUC τ,ss）。尽管阿托伐他汀降低了扎斯塔普赞的稳态峰浓度，但总暴露量得以保留，这一模式与吸收动力学改变一致，但未确立具体机制。由于未测量胃内pH值，扎斯塔普赞稳态峰浓度降低的药效学意义仍不确定。这些药代动力学研究结果提示，在所述研究条件下无需调整阿托伐他汀剂量。 扎斯塔普赞是一种新型抑酸药物。在真实世界临床实践中，对于需要治疗高胆固醇水平或心血管风险的患者，抑酸药物可能与他汀类药物（如阿托伐他汀）联合使用。本研究评估了扎斯塔普赞和阿托伐他汀重复联合给药5天是否影响机体对任一药物的处理。健康的韩国男性受试者分别单独接受阿托伐他汀、单独接受扎斯塔普赞，以及两药联合使用。所有24名入组受试者均为男性。扎斯塔普赞未显著改变阿托伐他汀或其活性代谢物的总暴露量。阿托伐他汀降低了扎斯塔普赞的血浆峰浓度，而扎斯塔普赞在给药间隔内的总暴露量得以维持。由于未测量胃酸度，峰浓度降低对抑酸效果的重要性仍不确定。未发现严重安全性问题。这些药代动力学研究结果不支持在联合用药时需要调整阿托伐他汀剂量。 在所研究的条件下使用zastaprazan。由于本研究仅纳入了健康男性，因此在女性和患有酸相关疾病或心血管疾病的患者中进行验证，将有助于增强研究结果的普适性。
完整摘要 · 英文原文
PURPOSE: Zastaprazan is a novel potassium-competitive acid blocker with CYP3A-mediated metabolism, whereas atorvastatin undergoes CYP3A4- and transporter-mediated disposition. Because these drugs may be co-administered and their net interaction cannot be inferred from shared metabolic pathways alone, this study evaluated their steady-state pharmacokinetic drug-drug interaction. PARTICIPANTS AND METHODS: This open-label, fixed-sequence, three-period, multiple-dose study included healthy Korean men. Participants received atorvastatin 40 mg once daily, zastaprazan 20 mg once daily, and concomitant atorvastatin and zastaprazan, each for 5 consecutive days, under steady-state conditions. Plasma concentrations of zastaprazan, atorvastatin, and 2-hydroxyatorvastatin were measured, and geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for C max,ss and AUC τ,ss. RESULTS: Twenty-four healthy Korean men received at least one dose of a study drug, and 22 were included in the pharmacokinetic analysis. Atorvastatin decreased zastaprazan C max,ss by approximately 26% (GMR, 0.740; 90% CI, 0.655-0.836), whereas AUC τ,ss was preserved (GMR, 1.054; 90% CI, 0.927-1.198). Zastaprazan did not meaningfully alter atorvastatin exposure (C max,ss GMR, 0.982; 90% CI, 0.806-1.195; AUC τ,ss GMR, 1.029; 90% CI, 0.944-1.122). The AUC τ,ss of 2-hydroxyatorvastatin showed a modest decrease (GMR, 0.940; 90% CI, 0.889-0.994) that remained within the predefined conventional reference range. Co-administration was generally well tolerated, with no serious adverse events or adverse event-related discontinuations. CONCLUSION: Zastaprazan did not meaningfully alter atorvastatin C max,ss or AUC τ,ss under the studied conditions. Although atorvastatin reduced zastaprazan C max,ss, total exposure was preserved, a pattern consistent with altered absorption kinetics without establishing a specific mechanism. The pharmacodynamic significance of the lower zastaprazan C max,ss remains uncertain because intragastric pH was not measured. These pharmacokinetic findings do not suggest a need for atorvastatin dose adjustment under the studied conditions. Zastaprazan is a new acid-suppressive medicine. In real-world practice, acid-reducing medicines may be co-administered with statins such as atorvastatin in people requiring treatment for high cholesterol levels or cardiovascular risk. This study evaluated whether repeated 5-day co-administration of zastaprazan and atorvastatin affected how the body handled either drug. Healthy Korean men received atorvastatin alone, zastaprazan alone, and both medicines together. All 24 enrolled participants were men. Zastaprazan did not meaningfully alter the overall exposure to atorvastatin or its active metabolite. Atorvastatin lowered the peak plasma concentration of zastaprazan, while total zastaprazan exposure over the dosing interval was maintained. Because stomach acidity was not measured, the importance of the lower peak concentration for acid suppression remains uncertain. No serious safety concerns were identified. These pharmacokinetic findings do not support a need for atorvastatin dose adjustment when co-administered with zastaprazan under the studied conditions. Because the study included only healthy men, confirmation in women and in patients with acid-related or cardiovascular disease would strengthen the generalizability of the findings.