多水平模型在生物等效性评价中的应用（Ⅱ）

Application of multilevel models in the evaluation of bioequivalence （ Ⅱ ）

探讨多变量多水平模型在生物等效性评价中的应用价值。以4×4交叉试验设计的国产和进口罗格列酮药物生物等效性评价为研究实例，研究多变量多水平模型在同时评价多个指标等效性时方差分量的分解方式，并探讨在多变量多水平框架下评价平均、群体和个体等效性评价的可行性。多变量多水平模型考虑了罗格列酮药物指标In（AUC）和In（Gmax）的相关性，在两个指标出现一个平均等效而另一个平均不等效的矛盾结果时，通过联合检验最终判断两个指标联合具有平均等效性。根据多变量多水平模型方差分量，进一步获得了国产和进口罗格列酮药物具有群体和个体等效性。结论：多变量多水平模型可将多个相关指标纳入同一个模型中，考虑了指标之间的相关性，可改善误差结构，对同时评价多个指标生物等效性提供了统计学方法的发展思路。

The main purpose of this paper is to explore the applicability of multivariate multilevel models for bioequivalence evaluation. Using an example of a 4 × 4 cross-over test design in evaluating bioequivalence of homemade and imported rosiglitazone maleate tablets, this paper illustrated the multivariate-model-based method for partitioning total variances of In （AUC） and In （Cmax） in the framework of multilevel models. It examined the feasibility of multivariate multilevel models in directly evaluating average bioequivalence （ABE） , population bioequivalence （PBE） and individual bioequivalenc （IBE）. Taking into account the correlation between In （AUC） and In （Cmax） of rosiglitazone maleate tablets, the proposed models suggested no statistical difference between the two effect measures in their ABE bioequivalence via joint tests, whilst a contradictive conclusion was derived based on univariate multilevel models. Furthermore, the PBE and IBE for both In （AUC） and In （Cmax） of the two types of tablets were assessed with no statistical difference based on estimates of variance components from the proposed models. Multivariate multilevel models could be used to analyze bioequivalence of multiple effect measures simultaneously and they provided a new way of statistical analysis to evaluate bioequivalence.