利用人口药代动力学和儿科患者恩替卡韦的药效学分析简化

StephenW

Clin Pharmacokinet. 2016 Jun 18. [Epub ahead of print]
Using Population Pharmacokinetic and Pharmacodynamic Analyses of Entecavir in Pediatric Subjects to Simplify Dosing Recommendations.Chan P1, Mould DR2, Tarif MA3, Reynolds L3, LaCreta F3, Bertz R3, Bifano M3.
Author information

• 1Bristol-Myers Squibb, Route 206 & Province Line Road, Lawrenceville, NJ, 08648, USA. [email protected].
• 2Projections Research, Inc., Phoenixville, PA, USA.
• 3Bristol-Myers Squibb, Route 206 & Province Line Road, Lawrenceville, NJ, 08648, USA.
  

AbstractBACKGROUND: Entecavir is an orally administered guanosine nucleoside analog with activity against hepatitis B virus (HBV) polymerase, which is approved for the treatment of chronic hepatitis B (CHB) infection in adults and children ≥2 years old (USA and EU).
OBJECTIVE: To develop simplified entecavir dosing recommendations for young children infected with CHB.
METHODS: Data from recent clinical trials were used to develop a population pharmacokinetic (PPK) model, which allowed us to estimate entecavir exposures in children and compare them to ranges known to be efficacious in adults. A population pharmacodynamic (PPD) model was generated to describe the concentration/effect relationship for entecavir in lamivudine treatment-naïve children. The PPK dataset comprised three pediatric cohorts: 2 to <6 years (n = 36); 6 to <12 years (n = 43); and 12 to <18 years (n = 74). Data from 177 adults were also included to enhance model stability and to aid in the covariate search.
RESULTS: Entecavir concentration-time profiles were well-described by a two-compartment model with first-order absorption and first-order elimination. Age was not a statistically significant covariate after accounting for weight. For the PPD model, the HBV DNA concentration following entecavir exposure was adequately described using a direct effect inhibitory maximum effect (E max) model with additive residual error.
CONCLUSION: Model-estimated, steady-state entecavir area under the concentration-time curve, in both the original (15 weight groups) and simplified (eight weight groups) pediatric dosing regimens, provided entecavir exposures consistent with those observed to be efficacious in adults, and resulted in the simplified dose algorithm for pediatric patients that is approved for the current entecavir label.

StephenW

临床Pharmacokinet。 2016年六月18 EPUB提前打印]
利用人口药代动力学和儿科患者恩替卡韦的药效学分析简化的推荐剂量。
陈P1，模具DR2，塔里夫MA3，雷诺L3，F3 LaCreta，Bertz R3，Bifano M3。
作者信息

    1Bristol-Myers Squibb公司，路线206省道线，劳伦斯维尔，NJ，08648，USA。 [email protected]。
    2Projections Research公司，菲尼克斯，PA，USA。
    3Bristol-Myers Squibb公司，路线206省道线，劳伦斯维尔，NJ，08648，USA。

抽象
背景：

恩替卡韦是一种口服鸟苷核苷类似物具有抗乙型肝炎病毒（HBV）聚合酶，它被批准用于成人和儿童≥2岁（美国和欧盟）的治疗慢性乙型肝炎（CHB）感染的活性。
目的：

制定感染乙肝幼儿简化恩替卡韦的推荐剂量。
方法：

从最近的临床试验数据被用来开发一个群体药代动力学（PPK）模型，它允许我们估计恩替卡韦暴露在儿童和他们比较，已知在成年人有效范围。被产生了一个群体药效学（PPD）模型来描述拉米夫定治疗，天真的孩子恩替卡韦的浓度/效应关系。该数据集PPK由三个同伙小儿2〜<6年（N = 36）; 6〜<12年（N = 43）;和12至<18年（N = 74）。从177名成人的数据也包括在内，以提高模型的稳定性，并在协查帮助。
结果：

通过与一级吸收和一级消除二室模型恩替卡韦浓度 - 时间曲线进行了很好的描述。年龄不占重量后，在统计学上显著协变量。对于PPD模式，恩替卡韦之后暴露HBV DNA浓度使用带有添加剂的残差产生直接的影响抑制最大效应（E最大值）模型充分描述。
结论：

模型估计的浓度 - 时间曲线下，稳态恩替卡韦区，在这两个原始（15重量组）和简化（8重量基）儿科给药方案，提供恩替卡韦暴露与这些观察一致，以在成人中有效的，并导致了被批准用于当前标签恩替卡韦小儿患者简化剂量算法。