Tamaki Yoko, Maema Kunio, Kakara Makoto, Fukae Masato, Kinoshita Ryoko, Kashihara Yushi, Muraki Shota, Hirota Takeshi, Ieiri Ichiro
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Yame General Hospital, Fukuoka, Japan.
Drug Metab Pharmacokinet. 2018 Dec;33(6):264-269. doi: 10.1016/j.dmpk.2018.08.002. Epub 2018 Aug 16.
The objective of the present study was to develop a population pharmacodynamic (PPD) model to describe the glycated hemoglobin (HbA1c)-lowering effects of metformin in type 2 diabetes mellitus patients with and without secondary failure and to characterize changes in HbA1c levels in the two subpopulations using a mixture model. Information on patients was collected retrospectively from electronic medical records. In this study, the mixture model was used to characterize the bimodal effects of metformin. A PPD analysis was performed using NONMEM 7.3.0. A physiological indirect response model, based on 829 HbA1c levels of 69 patients, described the time course for the HbA1c-lowering effects of metformin. Evidence for the different effectiveness of metformin subpopulations was provided using the mixture model. In the final PPD model, the inhibition effect was constant over a study duration in a patient subpopulation without secondary failure. In contrast, the inhibition effect decreased as a function of time after start of metformin treatment in a subpopulation with secondary failure. These results indicated that HbA1c improvements appeared to deteriorate over time in patients with secondary failure. In a PPD analysis of metformin, it was possible to assign patients with secondary failure using the mixture model.
本研究的目的是建立一个群体药效学（PPD）模型，以描述二甲双胍对有或无继发性失效的2型糖尿病患者糖化血红蛋白（HbA1c）的降低作用，并使用混合模型描述两个亚组中HbA1c水平的变化。患者信息通过回顾性收集电子病历获得。在本研究中，混合模型用于描述二甲双胍的双峰效应。使用NONMEM 7.3.0进行PPD分析。基于69例患者的829个HbA1c水平建立的生理间接反应模型，描述了二甲双胍降低HbA1c作用的时间过程。使用混合模型提供了二甲双胍亚组不同有效性的证据。在最终的PPD模型中，在无继发性失效的患者亚组中，抑制作用在研究期间保持恒定。相比之下，在有继发性失效的亚组中，抑制作用在二甲双胍治疗开始后随时间下降。这些结果表明，继发性失效患者的HbA1c改善似乎随时间恶化。在二甲双胍的PPD分析中，使用混合模型可以区分有继发性失效的患者。
