目的:伏立康唑(VCZ)的治疗药物监测(TDM)对于所有侵袭性真菌感染(IFIs)的儿科患者是强制性的。狭窄的治疗指数,VCZ药代动力学的个体差异,和遗传多态性导致在该人群中在治疗期间达到治疗浓度具有挑战性。
方法:该研究包括44名接受VCZ治疗的IFIs患儿。通过HPLC-FLD方法测定的VCZ器皿的谷浓度(Cfuth)。通过PCR-RFLP鉴定CYP2C19*2和CYP2C19*17基因多态性。分析了基因多态性与VCZCtrugh的相关性。此外,剂量等因素的影响,年龄,性别,给药途径,和药物相互作用进行了调查。
结果:VCZ以14.7mg/kg/天的中位维持剂量口服和静脉内给药,中位给药10天。VCZCtrough变化很大,范围为0.1至6.8mg/L。只有45%的儿童达到了治疗范围。Ctrugh和剂量之间没有显着关联,年龄,性别,给药途径,和伴随的药物。变异表型正常(NM)的频率,中间(IM),快速(RM)和超快速代谢(UM)占41%,18%,28%,13%,分别。与RM相比,NM和IM组的VCZ表达明显更高,和UM组。
结论:VCZ的Ctrugh的特征是个体间的变异性和患者达到治疗范围的低比率。在儿童中,VCZCtrugh和CYPC19表型之间存在显着关联。重复TDM和基因分型的组合对于确保有效治疗是必要的。
OBJECTIVE: Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population.
METHODS: The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (Ctrough) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR-RFLP. The correlation between polymorphisms and VCZ Ctrough was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated.
RESULTS: VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ Ctrough was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between Ctrough and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. Ctrough of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups.
CONCLUSIONS: The Ctrough of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ Ctrough and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment.