Department of Clinical Drug Metabolism, Merck Research Laboratories, West Point, PA 19486-0004, USA.
Am J Ther. 2009 Sep-Oct;16(5):379-84. doi: 10.1097/MJT.0b013e318197c59d.
Flushing symptoms limit the use of niacin as an effective treatment for dyslipidemia; laropiprant, a prostaglandin D2 receptor subtype 1 antagonist, reduces niacin-induced flushing and is being developed in combination with niacin. The aims of this study were to both determine the effect of renal insufficiency on plasma pharmacokinetics of laropiprant and to assess safety and tolerability in patients with severe renal insufficiency. This open-label study compared the pharmacokinetics of a single laropiprant 40-mg dose in 8 nondialyzed, severe renal insufficiency patients (RIs) with healthy matched subjects (HSs) (24-hour creatinine clearance <30 mL/min/1.73 m(2) and >80 mL/min/1.73 m(2) for RIs and HSs, respectively). In RIs, laropiprant was well tolerated and the area under the concentration time curve (AUC(0-infinity)) was modestly higher (ratio of geometric least-squares means [GMR] for RIs to HSs was 1.58; 90% confidence interval [CI], 1.06-2.35); neither the maximum laropiprant plasma concentration (C(max)) nor the time to C(max) (T(max)) was significantly affected. The apparent terminal half-life (t(1/2)) was 26.0 and 14.8 hours for RIs and HSs, respectively (P = 0.007). Similarly, for the inactive laropiprant glucuronide metabolite, the GMR for AUC(0-infinity) was 2.17 (90% CI, 1.44-3.27), and the apparent t(1/2) values were 25.3 to 14.5 hours (P = 0.037) in RIs and HSs, respectively. Renal insufficiency had no clinically significant effect on laropiprant pharmacokinetics. Because niacin and its metabolites are excreted through the kidneys, the combination of niacin with laropiprant should be used with caution in patients with renal impairment.
潮红症状限制了烟酸作为治疗血脂异常的有效药物；前列腺素 D2 受体亚型 1 拮抗剂拉罗匹仑可减少烟酸引起的潮红，目前正在与烟酸联合开发。本研究旨在确定肾功能不全对拉罗匹仑血浆药代动力学的影响，并评估严重肾功能不全患者的安全性和耐受性。这项开放标签研究比较了 8 名未透析的严重肾功能不全患者（RI）和健康匹配受试者（HS）单次服用 40mg 拉罗匹仑的药代动力学（RI 的 24 小时肌酐清除率 <30ml/min/1.73m2，HS 的为 >80ml/min/1.73m2）。在 RI 中，拉罗匹仑耐受良好，浓度时间曲线下面积（AUC（0-无穷大））略高（RI 与 HS 的几何均数比[GMR]为 1.58；90%置信区间[CI]，1.06-2.35）；拉罗匹仑最大血浆浓度（C（max））和达峰时间（T（max））均无显著影响。RI 和 HS 的表观终末半衰期（t1/2）分别为 26.0 和 14.8 小时（P=0.007）。同样，对于无活性的拉罗匹仑葡萄糖醛酸代谢物，AUC（0-无穷大）的 GMR 为 2.17（90%CI，1.44-3.27），表观 t1/2 值分别为 25.3 至 14.5 小时（P=0.037）在 RI 和 HS 中。肾功能不全对拉罗匹仑的药代动力学无明显临床影响。由于烟酸及其代谢物通过肾脏排泄，因此在肾功能受损的患者中，应谨慎将烟酸与拉罗匹仑联合使用。
