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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib
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Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

机译：Capecitabine和Cyp2C9衬底之间的长期药代动力学相互作用，Celecoxib

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Abstract This study investigated the time course and magnitude of the pharmacokinetic interaction between capecitabine and the cytochrome P450 (CYP) 2C9 substrate celecoxib, with implications for coadministration of fluoropyrimidines with CYP2C9 substrates such as warfarin. Patients received celecoxib 200 mg orally twice daily continuously, with capecitabine (1000 mg/m 2 orally twice daily for 14 days every 21 days) starting 7 days later. Assessment of the drug‐drug interaction (DDI) potential was performed using equivalence testing, which assumes that there is no clinically relevant DDI when the calculated 90% confidence intervals (CIs) of the drug exposure ratios fall within the range of 0.80 to 1.25. Comparison of steady‐state pharmacokinetic parameters of celecoxib between day 7 (cycle 0, celecoxib only) and day 14 (cycle 1, celecoxib + capecitabine) showed geometric mean ratios of 1.24 (90%CI, 1.04‐1.49), 1.30 (1.11‐1.53) and 1.28 (1.11‐1.47) for maximum plasma concentration, minimum plasma concentration, and area under the concentration‐time curve from time zero to 8 hours, respectively. Comparison of day 7 vs day 21 (cycle 1, after 1 week washout of capecitabine) showed a further increase in the geometric mean ratio of maximum plasma concentration (1.39; 90%CI, 1.16‐1.66), minimum plasma concentration (1.53; 1.10‐2.12) and area under the concentration‐time curve from time zero to 8 hours (1.41; 1.19‐1.68). Because the 90%CIs fell outside the prespecified equivalence margin, we conclude that coadministration results in a DDI (increased celecoxib exposure) that persists for at least 7 days after capecitabine discontinuation. Close monitoring should be undertaken when administering fluoropyrimidines with CYP2C9 substrates with narrow therapeutic indexes while also weighing the benefits and risks for individual patients.
机译：摘要本研究研究了Capecitabine和细胞色素P450（CYP）2C9衬底梭菌之间的药代动力学相互作用的时间过程和大小，具有用于CYP2C9诸如华法林的CYP2C9基材的氟嘧啶的共同分析。 7天后，患者每天每天每天两次服用塞克西昔米200毫克，每天两次，每天两次（每21天每天两次，每21天每天21天）。使用当量测试进行药物 - 药物相互作用（DDI）电位的评估，这假设当计算出的药物暴露比率的90％置信区间（CIS）下降到0.80至1.25的范围内时，没有临床相关的DDI。在第7天（周期0，Celecoxib）和第14天（循环1，Celecoxib + Capecitabine）之间的稳态药代动力学参数的比较显示为1.24（90％CI，1.04-1.49），1.30（1.11- 1.53）和1.28（1.11-1.47），用于最大血浆浓度，最小血浆浓度和浓度 - 时间曲线的面积分别从0到8小时。比较第7天的第21天（循环1，1周后Capecitabine后）显示出最大血浆浓度的几何平均比（1.39; 90％Ci，1.16-1.66），最小血浆浓度（1.53; 1.10 -2.12）和浓度 - 时间曲线下的区域从0到8小时（1.41; 1.19-1.68）。由于90％的CIS落在预先预定的等价边缘之外，因此得出结论，共同分子在Capecitabine停止后至少7天内持续存在的DDI（Celecoxib暴露）。应对CYP2C9底物用狭窄治疗指标进行氟嘧啶时，应进行密切监测，同时称重个体患者的益处和风险。

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