Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA.
Antimicrob Agents Chemother. 2011 Jan;55(1):184-9. doi: 10.1128/AAC.01078-10. Epub 2010 Oct 25.
The approved treatment dose of intravenous voriconazole is a weight-based dose of 4 mg/kg of body weight twice daily; the approved oral dosing is fixed at 200 mg twice daily. In our institution, patients frequently receive oral high-dose voriconazole at 4 mg/kg twice daily. It is unknown if higher doses are associated with increased hepatotoxicity. A retrospective cohort study of patients treated with oral voriconazole for presumed invasive fungal infection for ≥7 days was completed. Patients receiving a fixed dose (i.e., labeled dose) were frequency matched and compared to those receiving a weight-based dose (i.e., high dose). The primary endpoint of hepatotoxicity was evaluated by using NCI Common Terminology Criteria (CTC) and components of liver enzymes measuring >3× the upper limit of normal (ULN) and >5× baseline measurements. Secondary endpoints included an incidence of other adverse drug events. Twenty-five labeled-dose and 84 high-dose voriconazole patients were studied. Liver enzyme abnormalities were similar between groups, with the exception of labeled-dose patients experiencing more alkaline phosphatase (ALP) CTC >2× the baseline (P = 0.02) and ALP levels >3× the ULN (P = 0.02). Treatment with high dose was associated with the discontinuation of voriconazole for practitioner attribution of adverse drug events (P = 0.03), although reasons varied and no commonality of biomarker abnormality was identified. Multivariate analysis revealed that the duration of therapy and higher mg/kg total daily doses as interval variables were predictive of some hepatotoxicity outcomes. No difference existed in liver abnormalities for high-dose voriconazole; however, higher mg/kg doses and a longer duration of therapy may be associated with hepatotoxicity.
静脉伏立康唑的批准治疗剂量为 4 毫克/千克体重，每日两次；批准的口服剂量为每日两次 200 毫克。在我们的机构中，患者经常接受口服高剂量伏立康唑，剂量为每日两次 4 毫克/千克。目前尚不清楚更高的剂量是否与肝毒性增加有关。一项对接受口服伏立康唑治疗疑似侵袭性真菌感染≥7 天的患者进行的回顾性队列研究完成了。接受固定剂量（即标签剂量）的患者与接受体重为基础剂量（即高剂量）的患者进行了频率匹配比较。肝毒性的主要终点通过 NCI 常见术语标准（CTC）和测量值超过正常值上限（ULN）3 倍和超过基线 5 倍的肝酶成分进行评估。次要终点包括其他药物不良反应的发生率。研究了 25 名接受标签剂量和 84 名接受高剂量伏立康唑的患者。两组间肝酶异常相似，除标签剂量患者碱性磷酸酶（ALP）CTC 高于基线 2 倍（P = 0.02）和 ALP 水平高于 ULN 3 倍（P = 0.02）外。由于医生归因于药物不良反应，高剂量组停用伏立康唑（P = 0.03），尽管原因各不相同，未发现生物标志物异常的共性。多变量分析显示，治疗持续时间和更高的毫克/千克每日总剂量作为间隔变量与某些肝毒性结果相关。高剂量伏立康唑无肝异常差异；然而，更高的毫克/千克剂量和更长的治疗持续时间可能与肝毒性有关。
