Population Pharmacokinetics of Prednisolone in Relation to Clinical Outcome in Children With Nephrotic Syndrome
Population Pharmacokinetics of Prednisolone in Relation to Clinical Outcome in Children With Nephrotic Syndrome
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DOI：
10.1097/ftd.0000000000000308
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发表时间：
2016-08-01
影响因子：
2.5
通讯作者：
Nauta, Jeroen
中科院分区：
文献类型：
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作者：
Teeninga, Nynke;Guan, Zheng;Nauta, Jeroen
背景：尽管有标准化的泼尼松龙治疗方案，肾病综合征（NS）儿童的复发率差异很大。关于泼尼松龙药代动力学 (PK) 与 NS 儿童临床反应之间关系的现有证据很少且有限。本研究的目的是基于我们之前的模型开发泼尼松龙的儿科流行药代动力学模型，该模型基于健康成人，使用 NS 儿童唾液测量，并将临床结果与泼尼松龙暴露的受试者间变异性相关联。 方法：确定了由 104 名缓解期 NS 儿童组成的明确的前瞻性队列中泼尼松龙的药代动力学。分析与复发模式和副作用相关的药代动力学参数。使用稀疏采样策略进行无创唾液泼尼松龙测量。采用群体药代动力学方法从唾液浓度-时间曲线得出表观清除率 (CL/F) 和表观分布容积 (V/F) 的个体估计值，然后计算游离泼尼松龙的曲线下面积 (AUC)。唾液中泼尼松龙的个体游离血清泼尼松龙暴露量源自唾液浓度-时间曲线。探索了 CYP3A4、CYP3A5、ABCB1、NR1L2 和 POR 的遗传多态性与 CL/F 受试者间变异性的关系。结果：发现 CL/F 存在中等个体间变异性（CV，44.7%）。与野生型相比，携带 1 或 2 个 ABCB1 3435C>T 等位基因的患者中 CL/F 的无法解释的随机受试者间变异性 (eta) 较低：中位数 -0.04（四分位距，-0.17 至 0.21）和 0.00（-0.11 至 0.16）与 0.17（-0.08 至 0.47）相比，P = 0.046。暴露于游离泼尼松龙与频繁复发或不良反应无关。结论：这项研究为通过唾液测量进行泼尼松龙药物监测的可能性提供了证据，这可能对儿科患者特别有用。然而，在研究的治疗剂量范围内观察到的泼尼松龙暴露量的变化并不被认为是 NS 儿童临床结果的主要决定因素。
Background:The relapse frequency in children with nephrotic syndrome (NS) is highly variable despite standardized prednisolone treatment regimens. Existing evidence on the relationship between prednisolone pharmacokinetics (PK) and clinical response in children with NS is scarce and limited. The aim of this study was to develop a pediatric popPK model for prednisolone based on our previous model based on healthy adults using salivary measurements in children with NS and to correlate clinical outcome with between-subject variability in prednisolone exposure.Methods:The pharmacokinetics of prednisolone in a well-defined, prospective cohort consisting of 104 children with NS while in remission was determined. Pharmacokinetic parameters were analyzed in relation to relapse patterns and side effects. Noninvasive salivary prednisolone measurements were performed using a sparse sampling strategy. A population pharmacokinetic approach was used to derive individual estimates of apparent clearance (CL/F) and apparent volume of distribution (V/F) from the salivary concentration-time curve, followed by calculation of the area under the curve (AUC) of free prednisolone. The individual free serum prednisolone exposure from prednisolone in saliva was derived from the salivary concentration-time curves. Genetic polymorphisms of CYP3A4, CYP3A5, ABCB1, NR1L2, and POR were explored in relation to between-subject variability of CL/F.Results:Moderate interindividual variability was found for CL/F (CV, 44.7%). Unexplained random between-subject variability (eta) of CL/F was lower in patients carrying 1 or 2 ABCB1 3435C>T alleles compared to wild type: median -0.04 (interquartile range, -0.17 to 0.21) and 0.00 (-0.11 to 0.16) versus 0.17 (-0.08 to 0.47), P = 0.046. Exposure to free prednisolone was not associated with frequent relapses or adverse effects.Conclusions:This study provides evidence for the possibility of prednisolone drug monitoring through salivary measurements and this may be of particular usefulness in pediatric patients. However, the observed variability in prednisolone exposure, in the therapeutic dose range studied, is not considered to be a major determinant of clinical outcome in children with NS.