Developmental pharmacokinetics of ciclosporin - a population pharmacokinetic study in paediatric renal transplant candidates
Developmental pharmacokinetics of ciclosporin - a population pharmacokinetic study in paediatric renal transplant candidates
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DOI：
10.1111/j.1365-2125.2007.03003.x
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发表时间：
2007-12-01
影响因子：
3.4
通讯作者：
Hoppu, K.
中科院分区：
文献类型：
--
作者：
Fanta, S.;Jonsson, S.;Hoppu, K.
目的 使用群体药代动力学模型来表征发育和人口因素对环孢素药代动力学变异性的影响。方法使用包含 162 名年龄为 0.36-17.5 岁的移植前儿童的数据集在 NONMEM 中进行药代动力学建模。环孢素分次静脉注射（3 mg·kg(-1)）和口服（10 mg·kg(-1)），连续24 h采血。结果一级吸收无滞后时间的三室模型最好地描述了环孢素的药代动力学。影响全身清除率 (CL) 和分布容积 (V) 的最重要协变量是体重（BW；异速缩放），导致未校正的环孢素 CL 存在四倍差异，环孢素 V 存在六倍差异。其他显着协变量（红细胞压积、血浆胆固醇和肌酐）估计解释了环孢素 CL 和 V 个体间差异的 20-30%。口服生物利用度或体重标准化 V 未见与年龄相关的变化。体重标准化 CL (CL/BW) 随着年龄的增长而下降，青春期前儿童（< 8 岁）的 CL/BW 比年龄较大的儿童高约 25%。异速体重 (BW3/4) 的 CL 正常化消除了其与年龄的关系。结论 CL 和异速体重之间的关系与相对肝脏大小逐渐减小直至成年值一致，并且从约 6-12 个月龄到成年肝脏中 CYP3A4 含量相对恒定。此前已知环孢素口服生物利用度表现出较大的个体差异，但不受年龄影响。这些发现可以使婴儿、儿童和青少年的环孢素剂量更好地个体化。
AimsTo use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin.MethodsPharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36-17.5 years. Ciclosporin was given intravenously (3 mg kg(-1)) and orally (10 mg kg(-1)) on separate occasions followed by blood sampling for 24 h.ResultsA three-compartment model with first-order absorption without lag-time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume (V) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V. The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20-30% of interindividual differences in CL and V of ciclosporin. No age-related changes in oral bioavailability or in BW-normalized V were seen. The BW-normalized CL (CL/BW) declined with age and prepubertal children (< 8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW3/4) removed its relationship to age.ConclusionsThe relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6-12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.