Hing Jeremy P, Woolfrey Steven G, Greenslade Dennis, Wright Peter M C
Department of Anaesthesia, University of Newcastle upon Tyne.
J Appl Toxicol. 2002 Nov-Dec;22(6):437-43. doi: 10.1002/jat.883.
The purpose of this study was to compare the ability of non-compartmental analysis and compartmental mixed effects modelling (MEM) to determine the existence and magnitude of exposure differences (i.e. exposure ratio estimates) between subsets of animals during destructive toxicokinetic studies. Data from five toxicokinetic studies of an experimental compound were analysed using a linear trapezoidal calculation of the area under the curve (non-compartmental analysis) or modelled using MEM. With the non-compartmental method the Bailer-Satterthwaite approximation was used to construct confidence intervals around the exposure estimates of each subset of animals and these were used to determine if exposure differed between the subsets. The MEM analyses were performed on the full datasets and on datasets with arbitrary reductions in the number of animal replicates. With MEM, additional model parameters were used to differentiate between subsets of animals, and were incorporated only if they were justified statistically. Estimates of the existence and magnitude of exposure differences between animal subsets were similar with the two techniques. The MEM analyses were influenced only marginally by substantial reductions in the number of animals studied and were less compromised by extremely limited or unbalanced data. These analyses show that MEM and non-compartmental methods are similarly effective at detecting exposure differences between animal subsets in toxicokinetic studies. Estimates provided by both methods were influenced by the degree of variance in the data. These results support the proposition that it may be possible to reduce the number of animals employed in toxicokinetic studies if MEM is used.
本研究的目的是比较非房室分析和房室混合效应建模（MEM）在确定破坏性毒代动力学研究中动物亚组之间暴露差异的存在和程度（即暴露比估计值）方面的能力。使用曲线下面积的线性梯形计算（非房室分析）对一种实验化合物的五项毒代动力学研究数据进行分析，或使用MEM进行建模。采用非房室方法时，使用Bailer-Satterthwaite近似法围绕每个动物亚组的暴露估计值构建置信区间，并用于确定亚组之间的暴露是否存在差异。MEM分析在完整数据集以及动物重复数量任意减少的数据集上进行。使用MEM时，额外的模型参数用于区分动物亚组，并且只有在统计学上合理时才纳入。两种技术对动物亚组之间暴露差异的存在和程度的估计相似。MEM分析仅受到所研究动物数量大幅减少的轻微影响，并且较少受到极其有限或不平衡数据的影响。这些分析表明，在毒代动力学研究中，MEM和非房室方法在检测动物亚组之间的暴露差异方面同样有效。两种方法提供的估计值均受到数据方差程度的影响。这些结果支持这样一种观点，即如果使用MEM，有可能减少毒代动力学研究中使用的动物数量。
