Division of Hematology and Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
Division of Blood and Marrow Transplant, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
Antimicrob Agents Chemother. 2021 Aug 17;65(9):e0062321. doi: 10.1128/AAC.00623-21.
Prophylactic voriconazole use is recommended for children undergoing hematopoietic cell transplantation (HCT). Dosing considerations are essential, due to the narrow therapeutic window of voriconazole. Known covariates do not sufficiently explain the large interindividual pharmacokinetic (PK) variability of voriconazole. Moreover, knowledge of voriconazole PK for age <2 years is limited. We investigated genetic and clinical covariate associations with voriconazole interindividual PK variability and subsequently simulated dosing regimens in children. This study was conducted as part of a single-institution, phase I study of intravenous voriconazole therapy for children undergoing HCT. We conducted a population PK analysis and tested covariate effects on voriconazole PK, including 67 genetic variants and clinical variables. We analyzed plasma voriconazole and -oxide metabolite concentrations from 58 children <21 years of age (including 12 children <2 years of age). A two-compartment parent mixed linear/nonlinear model best described our data. The CYP2C19 phenotype and body weight were significant covariates ( < 0.05 for both). Our model performance for age <2 years was comparable to that for other age groups. Simulation of the final model suggested the following doses to attain target steady-state trough concentrations of 1.5 to 5.0 mg/liter for the CYP2C19 normal phenotype: 16 mg/kg (weight of <15 kg), 12 mg/kg (weight of 15 to 30 kg), or 10 mg/kg (weight of >30 kg); doses were 33 to 50% lower for CYP2C19 poor/intermediate phenotypes and 25 to 50% higher for CYP2C19 rapid/ultrarapid phenotypes. We propose a new starting-dose regimen, combined with therapeutic drug monitoring, for intravenous voriconazole therapy in children of all ages. Future studies should validate this dosing regimen.
预防使用伏立康唑推荐用于接受造血细胞移植（HCT）的儿童。由于伏立康唑的治疗窗狭窄，因此剂量考虑至关重要。已知的协变量并不能充分解释伏立康唑个体间药代动力学（PK）的巨大变异性。此外，关于年龄<2 岁的儿童伏立康唑 PK 的知识有限。我们研究了遗传和临床协变量与伏立康唑个体间 PK 变异性的关系，随后模拟了儿童的给药方案。本研究是作为一项单机构、接受 HCT 的儿童静脉用伏立康唑治疗的 I 期研究的一部分进行的。我们进行了群体 PK 分析，并测试了伏立康唑 PK 的协变量效应，包括 67 个遗传变异和临床变量。我们分析了 58 名年龄<21 岁的儿童（包括 12 名年龄<2 岁的儿童）的血浆伏立康唑和 -氧化物代谢物浓度。两室母体混合线性/非线性模型最能描述我们的数据。CYP2C19 表型和体重是重要的协变量（两者均<0.05）。我们对年龄<2 岁的模型性能与其他年龄组相当。最终模型的模拟表明，要达到 CYP2C19 正常表型的目标稳态谷浓度 1.5 至 5.0 mg/L，需要以下剂量：体重<15kg 时 16mg/kg，体重 15 至 30kg 时 12mg/kg，体重>30kg 时 10mg/kg；对于 CYP2C19 差/中间表型，剂量降低 33%至 50%；对于 CYP2C19 快/超快表型，剂量增加 25%至 50%。我们提出了一种新的起始剂量方案，结合治疗药物监测，用于所有年龄段儿童的静脉用伏立康唑治疗。未来的研究应验证这种给药方案。
