儿童伏立康唑治疗药物浓度监测的临床意义

Clinical significance of therapeutic drug monitoring for children in China treated with voriconazole

目的:本研究拟评估伏立康唑治疗药物浓度监测在儿童侵袭性真菌感染治疗中的作用。方法:采集76例以常规推荐剂量静脉滴注或口服伏立康唑治疗侵袭性真菌感染患儿的血液标本共99份,应用高效液相色谱-质谱联用技术检测谷浓度。结果:测定伏立康唑谷浓度中位值为0.784μg·m L-1(0.025~9.910μg·m L-1),其中44例(44.4%)达到目标浓度范围(1~5.5μg·m L-1),给药剂量与血药浓度之间缺乏相关性(r=0.252,P=0.315)。个体间和个体内血药浓度变异系数分别为97.0%和69.6%。患儿年龄分布2个月~14岁,年龄<6岁的患儿与年龄>6岁的患者相比,谷浓度要达到目标范围需要给予更高剂量的伏立康唑(6.1 mg·kg-1/次vs.4.55 mg·kg-1/次,P<0.05)。谷浓度<1μg·m L-1的患儿治疗失败率高于成功率(58.8%vs.46.5%),但差异无统计学意义(P=0.390)。5名患儿治疗中监测谷浓度<1μg·m L-1且疗效不佳,通过提高给药剂量使谷浓度达1μg·m L-1以上,最终治疗有效。2例谷浓度≥5.5μg·m L-1的患儿均出现肝功能异常。结论:采用常规推荐剂量给药部分儿童难以达到伏立康唑的目标浓度。伏立康唑血药浓度在个体间和个体内均有较大的差异。低龄儿童要达到有效的伏立康唑血药浓度,往往需给予更高的用药剂量。开展伏立康唑药物浓度监测不仅可以保障患儿用药的安全性和有效性,同时可为合理制订我国儿童的伏立康唑初始治疗方案提供研究数据。

OBJECTIVE To evaluate the role of therapeutic drug monitoring on voriconazole in routine clinical practice of invasive fungal infection in children. METHODS Totally 99 blood samples were obtained from 76 patients receiving intravenous or oral voriconazole at routine doses. Trough voriconazole concentrations were quantified using high performance liquid chromatography-mass spectrometry. RESULTS The median of the detected trough concentration was 0. 784 μg·m L-1(0. 025–9. 910 μg/m L),44 patients(44. 4%) achieved the therapeutic range(1 –5. 5 μg·m L-1). There was no correlation between drug dose and measured voriconazole concentrations(r = 0. 252,P = 0. 315). Significant intra-and inter-patient variabilities of concentrations(97% and 69. 6%)were identified. The age was distributed from 2 months to 14 years old. Patients ≤6 years needed a significantly higher dose of voriconazole to achieved the therapeutic range compared to older patient groups(6. 1 mg·kg-1·dose-1 vs. 4. 55 mg·kg-1·dose-1,P <0. 05). Voriconazole level < 1 μg·m L-1 was more frequently observed in patients with treatment failure(failure vs. success,58. 8%vs. 46. 5%)(P = 0. 390). Children with monitoring valley concentration < 1 μg·m L-1 had poor curative effects,but after increasing the dose to make the concentration up to 1 μg·m L-1 above,final treatment became effective. Two cases were related to hepatotoxicity at concentrations above 5. 5 μg·m L-1. CONCLUSION Part of patients can not reach the therapeutic target with the dosage regimen recommended routinely. There are significant intra-and inter-patient variabilities of measured plasma concentrations. Younger patients need significantly higher doses of voriconazole to maintain the therapeutic trough levels compared to older children. Voriconazole TDMbased dosing adjustment is warranted for the safety and efficacy,and also can provide research data for optimizing dosage regimen in Chinese children.