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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Persistence of a Posaconazole‐Mediated Drug‐Drug Interaction With Ranolazine After Cessation of Posaconazole Administration: Impact of Obesity and Implications for Patient Safety
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Persistence of a Posaconazole‐Mediated Drug‐Drug Interaction With Ranolazine After Cessation of Posaconazole Administration: Impact of Obesity and Implications for Patient Safety

机译：持久性逆转波西唑唑管理后与牛唑啉的药物 - 药物相互作用：肥胖的影响和对患者安全的影响

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Abstract The antianginal agent ranolazine (Ranexa?) is metabolized primarily by cytochrome P450‐3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors, such as ketoconazole and posaconazole, is contraindicated due to risk of QT prolongation from high levels of ranolazine. This study evaluated the time course of recovery from the posaconazole drug interaction in normal‐weight and otherwise healthy obese subjects. Subjects received single doses of ranolazine in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation. With posaconazole coadministration, the geometric mean ratio of ranolazine area under the concentration curve (AUC) increased by a factor of 3.9 in normals and by 2.8 in obese subjects. Posttreatment washout of posaconazole was slow in normals (mean half‐life 36 hours) and further prolonged in obese subjects (64 hours). Recovery of ranolazine AUC toward baseline was delayed. AUC remained significantly elevated above baseline in normal‐weight and obese subjects for 7‐14 days after stopping posaconazole. Current product labeling does not address the need for delay or a reduced dose of ranolazine after discontinuation of a strong CYP3A inhibitor before ranolazine can be safely administered. We recommend that administration of ranolazine should be limited to 500 mg twice daily for 7 days after posaconazole discontinuation in patients with body mass index 18.5‐24.9 kg/m 2 and for 12 days in patients with body mass index ≥35 kg/m 2 after ranolazine is resumed.
机译：摘要抗亚基氨基唑啉（Ranexaα）主要由细胞色素P450-3A（CYP3A）酶代谢。由于高水平的ranolazine的QT延长风险，具有强大的CYP3A抑制剂，例如酮康唑和己酰基唑，如酮康唑和posaconazole的共同性。该研究评估了从正常重量和否则健康的肥胖受试者中恢复的时间进程。受试者在基线控制条件下接受单剂量的ranolazine，再次在Posaconazole的共同分析期间，在Posaconazole停止后2周的4个额外时间点。对于浓度曲线（AUC）下的ranolazine面积的几何平均比率在肥胖受试者中增加了浓度曲线（AUC）下的ranolazine面积的几何平均比率。 Posaconazole的后病理冲洗在法线中慢（平均半衰期36小时）并进一步延长肥胖的受试者（64小时）。回收雷诺嗪AUC朝向基线被推迟。在停止posaconazole后7-14天，在正常重量和肥胖受试者中，AUC在正常重量和肥胖受试者中仍然显着升高。目前的产品标签没有解决在可以安全地施用ranolazine之前停止在雷诺嗪的强CYP3A抑制剂后延迟或减少剂量的ranolazine。我们建议牛唑嗪的施用应每天两次限制在体重指数18.5-24.9 kg / m 2患者的患者后7天，体重指数≥35kg/ m 2的患者≥35kg/ m 2≥35kg/ m 2≥35kg/ m 2≥35kg/ m 2的患者每天7天。雷诺嗪恢复了。

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