A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study

Abstract

Background: The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers.

Methods: A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated.

Results: The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·μg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms.

Conclusions: This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin.

Trial registration: ClinicalTrials.gov NCT02712619.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. CONSORT flowchart.

Fig 2. Mean concentration profile of metformin administered at 250 mg (Δ) and 1000 mg (●).

(Inlet: log-linear scale; error bars present standard deviation).

Fig 3. Relationships between pharmacokinetic-pharmacodynamic parameters after metformin administration at 250 mg (triangle) and 1000 mg (circle). Reduction in (a) AUG0-3h, (b) Gmax, and (c) PP2 versus AUC0-12h; reduction in (d) AUG0-3h, (e) Gmax, and (f) PP2 versus Cmax.

(The solid lines and dashed lines represent the linear and quadratic models, respectively. The black circle represents data included in the linear regression at high exposure. P-values are from the F-tests, and r2 represents the coefficient of determination.).