Choi Suein, Jeon Sangil, Han Seunghoon
PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Department of Clinical Pharmacology and Therapeutics, The Catholic University of Korea Seoul St. Mary's Hospital, Seoul 06591, Korea.
Transl Clin Pharmacol. 2018 Mar;26(1):25-31. doi: 10.12793/tcp.2018.26.1.25. Epub 2018 Mar 16.
Metformin, an oral antihyperglycemic agent, is widely used as the first-line pharmacotherapy for type 2 diabetes mellitus (T2DM). It has been in use for several decades as numerous different formulations. However, despite its use, population pharmacokinetic (PK) modeling of metformin is not well developed. The aim of the present study was to evaluate the effect of formulation on PK parameters by developing a population PK model of metformin in Koreans and using this model to assess bioequivalence. We used a comparative PK study of a single agent and a fixed-dose combination of metformin in 36 healthy volunteers. The population PK model of metformin was developed using NONMEM (version 7.3). Visual predictive checks and bootstrap methods were performed to determine the adequacy of the model. The plasma concentration-time profile was best described by a two-compartment, first-order elimination model with first-order absorption followed by zeroorder absorption with lag time. From the covariate analysis, formulation had significant effect ( < 0.01) on relative bioavailability ( = 0.94) and first-order absorption constant ( = 0.83), but the difference was within the range of bioequivalence criteria. No other covariate was shown to have significant effect on PK parameters. The PK profile of the disposition phase was consistent with the published literature. However, in the present study, the multiple peaks found during the absorption phase implied the possible diversity of absorption PK profile depending on formulation or population. Unlike traditional bioequivalence analysis, the population PK model reflects formulation differences on specific parameters and reflected simulation can be performed.
二甲双胍是一种口服抗高血糖药物，作为2型糖尿病（T2DM）的一线药物治疗被广泛使用。它以多种不同剂型已使用了几十年。然而，尽管其被广泛使用，但二甲双胍的群体药代动力学（PK）模型尚未得到充分发展。本研究的目的是通过建立韩国人群二甲双胍的群体PK模型并使用该模型评估生物等效性，来评价剂型对PK参数的影响。我们对36名健康志愿者进行了单药二甲双胍和固定剂量复方二甲双胍的比较PK研究。使用NONMEM（版本7.3）建立了二甲双胍的群体PK模型。进行了可视化预测检查和自抽样法以确定模型的充分性。血浆浓度-时间曲线最好用具有一级吸收随后是零级吸收并伴有滞后时间的二室一级消除模型来描述。通过协变量分析，剂型对相对生物利用度（=0.94）和一级吸收常数（=0.83）有显著影响（<0.01），但差异在生物等效性标准范围内。没有其他协变量显示对PK参数有显著影响。处置相的PK曲线与已发表的文献一致。然而，在本研究中，吸收相发现的多个峰意味着吸收PK曲线可能因剂型或人群而异。与传统的生物等效性分析不同，群体PK模型反映了剂型在特定参数上的差异，并且可以进行反映性模拟。
