Global Clinical Pharmacology, Janssen Research & Development, Spring House, PA, USA.
Established Products, Janssen Research & Development UK, High Wycombe, UK.
J Clin Pharmacol. 2019 May;59(5):668-676. doi: 10.1002/jcph.1357. Epub 2018 Dec 11.
Dacogen, the formulated product of the pharmaceutically active agent decitabine (5 aza-2'-deoxycytidine), is approved for treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). The current analysis was performed to characterize the pharmacokinetics of decitabine in pediatric patients with AML and evaluate their consistency with the PK in adult patients. A population pharmacokinetic model was developed by pooling decitabine concentration-time data from 5 adult (AML and MDS) and 2 pediatric (AML) studies. A total of 840 concentration-time data points obtained from 71 adults and 28 pediatric subjects (1 to 16 years old) were available for analysis. A 2-compartment linear pharmacokinetic (PK) model with allometric scaling using body surface area accounting for body size adequately described the PK of decitabine. After accounting for body size, decitabine pharmacokinetics were not affected by age, sex, race, dosing regimen, renal function (creatinine clearance), bilirubin, or disease type (AML or MDS) and all PK parameters (including clearance, steady-state volume of distribution, maximum concentration, time to reach maximal concentration, and terminal half-life) were comparable between adult and pediatric patients. Simulated concentration-time profiles using the final population PK model suggested that decitabine exposure at steady state was similar in adults and pediatrics for a 20 mg/m decitabine dose administered as a 1-hour infusion once daily. The current analysis suggests that decitabine PK is similar in pediatric AML patients and a combined adult AML and MDS population.
地西他滨（5-氮杂-2′-脱氧胞苷）是达珂（Dacogen）的活性药物成分，已被批准用于治疗骨髓增生异常综合征（MDS）和急性髓细胞白血病（AML）。本分析旨在对 AML 儿科患者的地西他滨药代动力学特征进行描述，并评估其与成人患者药代动力学的一致性。通过汇集来自 5 项成人（AML 和 MDS）和 2 项儿科（AML）研究的地西他滨浓度-时间数据，建立了群体药代动力学模型。共有 71 名成年和 28 名儿科患者（1 至 16 岁）的 840 个浓度-时间数据点可用于分析。使用基于体表面积的比例缩放法的 2 隔室线性药代动力学（PK）模型可充分描述地西他滨的 PK。在考虑到体型后，地西他滨的药代动力学不受年龄、性别、种族、给药方案、肾功能（肌酐清除率）、胆红素或疾病类型（AML 或 MDS）的影响，所有 PK 参数（包括清除率、稳态分布容积、最大浓度、达到最大浓度的时间和终末半衰期）在成年患者和儿科患者之间均具有可比性。使用最终群体 PK 模型模拟的浓度-时间曲线表明，对于每天 1 次、1 小时输注的 20mg/m 地西他滨剂量，稳态时地西他滨在成人和儿科患者中的暴露情况相似。本分析表明，地西他滨 PK 在儿科 AML 患者和成人 AML 和 MDS 混合人群中相似。
