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目的采用多元多水平模型评价多奈哌齐口腔崩解片与普通片的生物等效性。方法 22例受试志愿者单次交叉口服多奈哌齐口腔崩解片(试验药)5 mg和多奈哌齐普通片(参比药)5 mg,采用高效液相色谱-串联质谱法测定给药后各时间点经时血药浓度,通过逐步建立模型来分析生物等效性。首先建立零模,探究ρ_(max)和AUC_(0-t)在阶段水平和个体水平的聚集性,从而进一步建立单元多水平模型。由于ρ_(max)和AUC_(0-t)两指标间存在相关性,因此最终建立多元多水平模型进行生物等效性的评价。结果模型显示多水平结构随机效应有显著差异(P<0.05),且ρ_(max)和AUC_(0-t)两指标在多水平中具有强相关性。试剂固定效应参数不存在显著差异,两指标90%联合置信区间在(-0.020,-0.007)之间。结论多元多水平模型用于生物等效性分析可有效解释变异,缩小置信区间范围。多奈哌齐口腔崩解片和多奈哌齐普通片生物等效。
Objective To evaluate the bioequivalence of donepezil orally disintegrating tablets and tablets by multivariate multi - level model. Methods Twenty-two volunteers were randomized to receive donepezil orally disintegrating tablets (test drug) 5 mg and donepezil normal tablets (reference drug) 5 mg in a single crossover test. The plasma samples were collected at various time points after administration by high performance liquid chromatography-tandem mass spectrometry Bioavailability was analyzed over time by establishing a model to analyze bioequivalence. Firstly, zero-modulus is established to explore the aggregation of ρ_max and AUC_ (0-t) at the stage and individual levels, so as to further establish a multi-level unit model. Due to the correlation between ρ max and AUC 0-t, a multivariate multi-level model was finally established to evaluate the bioequivalence. The results showed that there was a significant difference in the random effects of multi-level structure (P <0.05), and there were strong correlations between ρ max and AUC 0-t at multiple levels. There was no significant difference between the fixed effect parameters of the reagents, and the 90% joint confidence interval of the two indicators was between (-0.020, -0.007). Conclusion The multivariate multi-level model used in bioequivalence analysis can effectively explain the variation and narrow the range of confidence intervals. Donepezil orally disintegrating tablets and donepezil tablets are bioequivalent.