Abstract：
BACKGROUND: Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity.
METHODS: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination.
RESULTS: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher.
CONCLUSIONS: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.
METHODS: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination.
RESULTS: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher.
CONCLUSIONS: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.
摘要：
背景：已知伏立康唑药代动力学（PK）受CYP2C19等药物代谢酶的遗传多态性影响；然而，这些信息对于儿科人群是有限的。这项研究的主要目的是在患有恶性肿瘤或先天性免疫错误的日本儿童中建立一个结合CYP2C19表型的伏立康唑PK模型。
方法：CYP2C19基因型通过全基因组基因分型进行评估，定义如下：*17/*17：超类代谢物（URM），*1/*17：快速代谢（RM），*1/*1：正常代谢者（NM），*1/*2，*1/*3，*2/*17：中间代谢（IM），和*2/*2，*2/*3，*3/*3：代谢不良（PM）。进行群体PK分析。伏立康唑血清浓度曲线通过具有一阶吸收的两室模型描述，混合线性和非线性(米氏-Menten)消除。
结果：伏立康唑浓度数据来自60例患者，中位年龄为5.3岁。从CYP2C19基因型预测的表型是RM中的1(2%)，21例（35%）患者的NM，27例（45%）患者IM，11例（18％）患者的PM。基础疾病包括40例（67％）恶性肿瘤患者和18例（30％）先天性免疫错误患者。在CYP2C19表型中，预测PM显示完全抑制(Vmax抑制程度[Vmax，inh]=100%；Vmax=0）。Vmax的估计参数，γ-谷氨酰转肽酶（γ-GTP）2级或更高的患者的inh高0.8，当C反应蛋白（CRP）水平为2.0mg/dL或更高时，inh高2.7。
结论：CYP2C19遗传多态性，γ-GTP,CRP影响Vmax,伏立康唑在患有恶性肿瘤或先天性免疫错误的儿童中的应用。
方法：CYP2C19基因型通过全基因组基因分型进行评估，定义如下：*17/*17：超类代谢物（URM），*1/*17：快速代谢（RM），*1/*1：正常代谢者（NM），*1/*2，*1/*3，*2/*17：中间代谢（IM），和*2/*2，*2/*3，*3/*3：代谢不良（PM）。进行群体PK分析。伏立康唑血清浓度曲线通过具有一阶吸收的两室模型描述，混合线性和非线性(米氏-Menten)消除。
结果：伏立康唑浓度数据来自60例患者，中位年龄为5.3岁。从CYP2C19基因型预测的表型是RM中的1(2%)，21例（35%）患者的NM，27例（45%）患者IM，11例（18％）患者的PM。基础疾病包括40例（67％）恶性肿瘤患者和18例（30％）先天性免疫错误患者。在CYP2C19表型中，预测PM显示完全抑制(Vmax抑制程度[Vmax，inh]=100%；Vmax=0）。Vmax的估计参数，γ-谷氨酰转肽酶（γ-GTP）2级或更高的患者的inh高0.8，当C反应蛋白（CRP）水平为2.0mg/dL或更高时，inh高2.7。
结论：CYP2C19遗传多态性，γ-GTP,CRP影响Vmax,伏立康唑在患有恶性肿瘤或先天性免疫错误的儿童中的应用。
