Yukyung Kim1,2, Hankil Son1, Sungkweon Cho1, Donghwan Lee1, Hyerang Roh1,2, Mijeong Son1,2, Young-A Heo1,2, Jaeyong Chung3 and Kyungsoo Park1
1Yonsei University College of Medicine, Seoul, Korea, 2Supported by Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea, 3Seoul National University Bundang Hospital, South Korea
Objectives: Although metformin is a widely used for the treatment of type II diabetes mellitus, only a few articles have reported the relationship among its plasma concentrations (PK), glucose-lowering effects (PD), and related covariates. This study investigates a model describing such relationship in metformin.
Methods: A total of 48 healthy Korean subjects were included in the analysis. For each subject, after an overnight fast, a 3-h oral glucose tolerance test (OGTT) was performed at 10 AM in Day 1 to obtain baseline glucose levels. Then, they received the 1st dose of metformin (1000 mg) at 8 PM. Next day, the 2nd dose of metformin (750 mg) was given at 8 AM, followed by the 2nd OGTT test conducted in a fasted state 2 hours after the 2nd dose. Metformin plasma concentrations were measured using LC-MS/MS. NONMEM 7.2 was used to analyze the data.
Results: Plasma concentrations of intrinsic glucose were described by a turnover model with negative feedback via a moderator controlling glucose homeostasis and those of extrinsic glucose from OGTT by one-compartment model, assuming intrinsic and extrinsic glucoses share disposition PK parameters. Then, metformin’s PK was described by a 2-compartment model with 1st-order absorption and PD by an Emax model inhibiting both intrinsic glucose production and extrinsic glucose appearance rates in the plasma. Parameter estimates of glucose were 126 L/hr, 70.9 L, 82.1 mg/dL, 3.03 hr and 1.44 hr for clearance, volume of distribution, baseline level, rate constant for feedback site and absorption rate constant for extrinsic glucose, and those of metformin were 94.2 L/hr, 158 L, 243 L, 42.8 L/hr, 0.547 h-1 and 21,400 ng/mL for clearance, volume of distribution of central and peripheral compartments, intercompartmental clearance, absorption rate constant, and IC50 respectively. No covariate was found significant in metformin’ PK or PD. These estimates yielded the baseline glucose production rate of 34.9 g/hr and the half-life of glucose for plasma and feedback site of 0.39 hr and 0.23 hr, respectively, and that of metformin 1.2 hr. The model performance was evaluated using visual predictive check.
Conclusions: Glucose concentrations from OGTT were well described by a turnover model with negative feedback and metformin’s glucose lowering effect by inhibiting glucose production and appearance rates. No covariate was found significant. To better understand PK-PD relationship of metformin, a clinical study in actual patients is needed.
References:
[1] Pharmacokinetic-pharmacodynamic modeling for the relationship between glucose-lowering effect and plasma concentration of metformin in volunteers, Lee SH et al., Arch Pharm Res. 2004 Jul;27(7):806-10
[2] An Integrated Model for Glucose and Insulin Regulation in Healthy Volunteers and Type 2 Diabetic Patients Following Intravenous Glucose Provocations, Silber HE et al., J Clin Pharmacol. 2007 Sep;47(9):1159-71
[3] Ch 3.11.9 Negative feedback via a moderator, p325:329, Pharmacokinetic and Pharmacodynamic Data Analysis: concepts and Applications, 4th edition by J Gabrielsson, D Weiner
Reference: PAGE 23 () Abstr 3148 [www.page-meeting.org/?abstract=3148]
Poster: Drug/Disease modeling - Endocrine