伏立康唑与苯妥英钠的联合应用：药代动力学相互作用、安全性及耐受性
Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration.
作者信息
Purkins Lynn, Wood Nolan, Ghahramani Parviz, Love Edward R, Eve Malcolm D, Fielding Anitra
机构信息
Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK.
出版信息
Br J Clin Pharmacol. 2003 Dec;56 Suppl 1(Suppl 1):37-44. doi: 10.1046/j.1365-2125.2003.01997.x.
AIMS
Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and, to a lesser extent, by CYP3A4. Phenytoin is an inducer of CYP3A4 activity, and a substrate and inducer of CYP2C9 and CYP2C19. The present studies investigated the pharmacokinetic interactions of voriconazole and phenytoin when coadministered.
METHODS
Two placebo-controlled parallel-group studies were conducted in healthy male volunteers. Study A was an open-label study and investigated the effect of phenytoin (300 mg once daily) on the steady-state pharmacokinetics of voriconazole (200 mg and 400 mg twice daily). Study B was a double-blind randomized study to investigate the effects of voriconazole (400 mg twice daily) on the steady-state pharmacokinetics of phenytoin (300 mg once daily). Cmax and AUCtau were compared at days 7, 21, and 28 (Study A), and at days 7 and 17 (Study B). All adverse events were recorded.
RESULTS
Study A: 21 subjects were evaluable (10 voriconazole + phenytoin, 11 voriconazole + placebo). For subjects receiving voriconazole (200 mg twice daily) plus phenytoin, the day 21/day 7 ratios for voriconazole Cmax and AUCtau were 60.7%[90% confidence interval (CI) 50.1, 73.6] and 35.9% (90% CI 29.7, 43.3), respectively. Adjusted for voriconazole + placebo, the ratios between the means were 50.7% (90% CI 38.8, 66.1) and 30.6% (90% CI 23.5, 39.7), respectively. When the dose of voriconazole was increased to 400 mg twice daily, the day 28/day 7 ratios for voriconazole Cmax and AUCtau were 134% (90% CI 89.2, 200) and 139% (90% CI 97.3, 199), respectively. Study B: 15 subjects were evaluable for pharmacokinetic assessments (six phenytoin + voriconazole, nine phenytoin + placebo). The ratios between the means for phenytoin + voriconazole/phenytoin + placebo on day 17 vs. day 7 were: phenytoin Cmax 167% (90% CI 144, 193) and phenytoin AUCtau 181% (90% CI 156, 210). All treatments were well tolerated: most adverse events were mild/moderate and transient.
CONCLUSIONS
Repeat dose administration of phenytoin decreased the mean steady-state Cmax and AUCtau of voriconazole by approximately 50% and 70%, respectively. Increasing the dose of voriconazole from 200 mg to 400 mg b.d. compensated for this effect. Repeat dose administration of 400 mg b.d. voriconazole increased the mean steady-state Cmax and AUCtau of phenytoin by approximately 70% and 80%, respectively. It is therefore recommended that plasma phenytoin concentrations are monitored and the dose adjusted as appropriate when phenytoin is coadministered with voriconazole.
目的
伏立康唑是一种新型三唑类抗真菌药物，通过细胞色素P450同工酶CYP2C9、CYP2C19代谢，在较小程度上也通过CYP3A4代谢。苯妥英是CYP3A4活性的诱导剂，也是CYP2C9和CYP2C19的底物及诱导剂。本研究调查了伏立康唑与苯妥英合用时的药代动力学相互作用。
方法
在健康男性志愿者中进行了两项安慰剂对照的平行组研究。研究A是一项开放标签研究，调查苯妥英（每日一次300mg）对伏立康唑（每日两次200mg和400mg）稳态药代动力学的影响。研究B是一项双盲随机研究，调查伏立康唑（每日两次400mg）对苯妥英（每日一次300mg）稳态药代动力学的影响。在第7、21和28天（研究A）以及第7和17天（研究B）比较了Cmax和AUCtau。记录所有不良事件。
结果
研究A：21名受试者可进行评估（10名伏立康唑+苯妥英，11名伏立康唑+安慰剂）。对于接受伏立康唑（每日两次200mg）加苯妥英的受试者，伏立康唑Cmax和AUCtau的第21天/第7天比值分别为60.7%[90%置信区间（CI）50.1,73.6]和35.9%（90%CI 29.7,43.3）。以伏立康唑+安慰剂为对照进行调整后，均值之间的比值分别为50.7%（90%CI 38.8,66.1）和30.6%（90%CI 23.5,39.7）。当伏立康唑剂量增加至每日两次400mg时，伏立康唑Cmax和AUCtau的第28天/第7天比值分别为134%（90%CI 89.2,200）和139%（90%CI 97.3,199）。研究B：15名受试者可进行药代动力学评估（6名苯妥英+伏立康唑，9名苯妥英+安慰剂）。苯妥英+伏立康唑/苯妥英+安慰剂在第17天与第7天的均值比值为：苯妥英Cmax 167%（90%CI 144,193），苯妥英AUCtau 181%（90%CI 156,210）。所有治疗耐受性良好：大多数不良事件为轻度/中度且短暂。
结论
重复给予苯妥英使伏立康唑的平均稳态Cmax和AUCtau分别降低约50%和70%。将伏立康唑剂量从每日两次200mg增加至400mg可弥补此效应。重复给予每日两次400mg伏立康唑使苯妥英的平均稳态Cmax和AUCtau分别增加约70%和80%。因此，建议在苯妥英与伏立康唑合用时监测苯妥英血浆浓度并酌情调整剂量。
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