Merck & Co, Inc, Whitehouse Station, New Jersey, USA.
J Clin Pharmacol. 2011 Nov;51(11):1561-70. doi: 10.1177/0091270010387141. Epub 2011 Jan 5.
Understanding how inhibition of cytochrome P4503A (CYP3A) affects the metabolism of a new drug is critical in determining if a clinically relevant drug interaction will occur. Diltiazem interaction studies assess a given compound's sensitivity to moderate CYP3A inhibition. The present study compared the effect different durations and formulations of diltiazem (extended release [XR] and conventional release [CR]) had on the single-dose pharmacokinetics of midazolam. The geometric mean ratio (GMR; midazolam + diltiazem(XR × 5 days)/midazolam + diltiazem(XR × 2 days)) for midazolam AUC(0-∞) was 0.98 (90% confidence interval [CI], 0.87, 1.10). The GMR (midazolam + diltiazem(XR × 2 days)/midazolam + diltiazem(CR × 2 days)) for midazolam AUC(0-∞) was 0.82 (90% CI, 0.73, 0.92). Simcyp simulations accurately predicted the observed clinical results only when a hepatic CYP3A degradation rate (k(deg)) different from that provided by the software was used. The data suggest that dosing diltiazem XR for 2 days predicts the change in midazolam AUC as reliably as 5 days of XR dosing and 2 days of CR dosing. In addition, the authors believe that a hepatic CYP3A kdeg of 0.03 h(-1) should be considered for future Simcyp studies.
了解细胞色素 P4503A（CYP3A）抑制如何影响新药的代谢对于确定是否会发生临床相关的药物相互作用至关重要。地尔硫䓬相互作用研究评估了给定化合物对中度 CYP3A 抑制的敏感性。本研究比较了不同持续时间和剂型的地尔硫䓬（延长释放[XR]和常规释放[CR]）对咪达唑仑单剂量药代动力学的影响。咪达唑仑 AUC（0-∞）的地尔硫䓬（XR × 5 天+咪达唑仑）/地尔硫䓬（XR × 2 天+咪达唑仑）的几何均数比值（GMR）为 0.98（90%置信区间[CI]，0.87，1.10）。咪达唑仑 AUC（0-∞）的地尔硫䓬（XR × 2 天+咪达唑仑）/地尔硫䓬（CR × 2 天+咪达唑仑）的 GMR 为 0.82（90%CI，0.73，0.92）。只有当使用不同于软件提供的肝 CYP3A 降解速率（kdeg）时，Simcyp 模拟才能准确预测观察到的临床结果。数据表明，地尔硫䓬 XR 给药 2 天预测咪达唑仑 AUC 的变化与 XR 给药 5 天和 CR 给药 2 天一样可靠。此外，作者认为，对于未来的 Simcyp 研究，应考虑肝 CYP3A kdeg 为 0.03 h（-1）。
