Transl Clin Pharmacol.  2018 Mar;26(1):25-31. 10.12793/tcp.2018.26.1.25.

Population pharmacokinetic analysis of metformin administered as fixed-dose combination in Korean healthy adults

• Choi S
• Jeon S
• Han S

• KMID: 2420304
• DOI: http://doi.org/10.12793/tcp.2018.26.1.25

Abstract

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 (p < 0.01) on relative bioavailability (F = 0.94) and first-order absorption constant (Ka = 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.

Keyword

Metformin; NONMEM; Korean; Pharmacokinetics

MeSH Terms

Absorption
Adult*
Biological Availability
Diabetes Mellitus, Type 2
Drug Therapy
Healthy Volunteers
Humans
Metformin*
Pharmacokinetics
Plasma
Therapeutic Equivalency
Metformin

Figure

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  Figure 1 Individual plasma concentration versus time plots of metformin. The bold red line is the median value; (A) single agent (B) FDC agent.

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  Figure 2 Metformin PK model. Ka, first-order absorption rate constant; F1, fraction of the dose absorbed through first-order absorption; D2, duration of zero-order absorption; ALAG2, lag time of zero-order absorption; CL/F, apparent clearance; Q/F, apparent intercompartmental clearance.

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  Figure 3 Basic goodness-of-fit plots of the final model. The black solid y=x or y=0 lines are included for reference. The bold red lines are the loess (local regression smoothing) trend lines.

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  Figure 4 Visual predictive checks (A) Metformin single agent (B) FDC agent; The circles represent the observed metformin concentrations. The dashed line and grey area represent the median and 90% prediction intervals of simulation, respectively.

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