• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Integrated pharmacokinetic-pharmacodynamic model for acetaminophen, ibuprofen, and placebo antipyresis in children.
【24h】

Integrated pharmacokinetic-pharmacodynamic model for acetaminophen, ibuprofen, and placebo antipyresis in children.

机译：儿童对乙酰氨基酚，布洛芬和安慰剂退热的综合药代动力学-药效学模型。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic-pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (microgram/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and Sigmoid Emax effect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlax, k alpha, beta, T1/2 beta, AUC0-infinity, Vd/F, and Clp/F) were not different than those reported previously, except the APAP k alpha was significantly lower. The link component yielded keos of 0.58 +/- 0.06 (mean +/- SE), 0.70 +/- 0.11 and 0.57 +/- 0.11 hr-1 for APAP, IBU05, and IBU10, respectively; the Sigmoid Emax component yielded EC50s (microgram/ml) and sigmoidicity (gamma) of 4.63 +/- 0.39 and 3.98 +/- 0.42 for APAP, 11.33 +/- 1.35 and 3.97 +/- 0.58 for IBU05 and 12.83 +/- 1.89 and 4.27 +/- 0.63 for IBU10. On visual inspection of the efficacy-time profiles of the febrile children, a number of them had an apparent linear function (slope; delta degree C/hr) and/or a sinusoidal cyclic function "confounding" standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (delta degree C/hr) and/or a sinusoidal cyclic function to the Sigmoid Emax component to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual delta degree Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBU AUC0-infinity was confirmed; doubling the dose from 5 to 10 mg/kg increased the AUC0-->infinity by only 1.5-fold. The confounding effect of initial temperature (Tempi) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p = 0.03) contribution of Tempi (but not age) on the value of the slope function was found. There was no consistent effect of age or Tempi on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age and Tempi was observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, and Tempi interacted with beta in a significant multiple linear relationship with AUC0-infinity. The effects of IBU dose, age, and Tempi are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified Sigmoid Emax effect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempi on the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition to Tempi. A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.
机译：对于儿童有解热解毒作用的描述性资料。但是，链接的药代动力学-药效学（PK / PD）模型对于了解高热儿童的退热药作用至关重要。对先前报告的来自178名接受单次口服对乙酰氨基酚（APAP）（12.5 mg / kg），布洛芬（IBU）（5或10 mg / kg）或安慰剂的发热儿童的数据进行了检查。给药后长达12小时，测量APAP和IBU的直肠温度和血浆水平（微克/毫升）。将非线性回归分析应用于这些测量结果，并在102/153名接受APAP或IBU的高热儿童中获得了一个完整的单室PK，链接和Sigmoid Emax效应模型的同步解决方案。 PK参数（tlax，k alpha，β，T1 / 2 beta，AUC0-infinity，Vd / F和Clp / F）与以前报告的参数相同，只是APAP k alpha显着降低。对于APAP，IBU05和IBU10，链接分量产生的keos分别为0.58 +/- 0.06（平均+/- SE），0.70 +/- 0.11和0.57 +/- 0.11 hr-1;乙状结肠Emax成分的EC50（微克/毫升）和乙状结肠（γ）对于APAP为4.63 +/- 0.39和3.98 +/- 0.42，对于IBU05为11.33 +/- 1.35和3.97 +/- 0.58和12.83 +/- 1.89和IBU10的4.27 +/- 0.63。通过对发热儿童的疗效时间曲线进行目视检查，他们中的许多人具有明显的线性函数（斜率; delta度C / hr）和/或正弦循环函数“混淆”了PD分析的标准方法。因此，给予APAP或IBU的91/102儿童的温度曲线需要向Sigmoid Emax分量增加一个斜率（δC / hr）和/或一个正弦循环函数，以令人满意地拟合数据。接受安慰剂的所有22名儿童在其PD模型中也需要斜率和/或循环函数。安慰剂组的残留增量度Cs（观察到的预测值）与0没有显着差异。因此，未观察到安慰剂的退热作用。证实了IBU AUC0-无穷大的剂量依赖性;将剂量从5 mg / kg加倍到10 mg / kg，AUC0->无穷大仅增加1.5倍。还证实了初始温度（Tempi）对除安慰剂以外的所有治疗组的解热功效的混杂影响，也揭示了非线性药效学。发现Tempi（而不是年龄）对斜率函数值的显着贡献（p = 0.03）。年龄或Tempi对解热综合模型的循环成分没有一致的影响。此外，在接受IBU的患者中，观察到年龄和Tempi的多重线性关系，其中包含大量的PK，链接和PD变量。剂量，年龄和Tempi与β相互作用，与AUC0-infinity呈显着的多重线性关系。 IBU剂量，年龄和Tempi的影响无处不在，并在导致PD反应的事件链中逐渐扩散。发热的病因可产生斜率函数，其斜率的大小可能部分归因于潜在的疾病。在某些情况下，循环功能可以通过温度调节来解释。无论其原因如何，都混淆了对药物作用的分析，并使简单的，未经修饰的Sigmoid Emax效应模型不能令人满意地解释解热药物的作用。 Tempi对退热药物反应强度的影响也是一个发现，对退热药物的PD研究有重大影响。在接受IBU的儿童中，除Tempi外，剂量和年龄也是混杂因素。在为高热儿童开发这些退热药的适当给药方案时，必须考虑多种协变量。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号