A population pharmacokinetic (PK) model of metformin regarding immediate and extended release formulations under fasted and fed conditions
Nina Scherer (1), Christiane Dings (1), Jan Freijer (2), Valerie Nock (2), Thorsten Lehr (1)
(1) Clinical Pharmacy, Saarland University, Saarbruecken, Germany, (2) Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
Objectives: Metformin is a widely used biguanide glucose lowering agent and used as the first-line treatment for type 2 diabetes mellitus [1]. The available PK data of metformin indicates a high interindividual and intraindividual variability. We aimed to develop a mathematical model describing the PK of metformin after single and multiple dose of different formulations, and to determine the effect of covariates.
Methods: Metformin plasma concentration-time profiles and corresponding urinary data were used from four clinical phase I trials in healthy adults performed by Boehringer Ingelheim. Volunteers received immediate (IR) or extended release (ER) formulations between 850 mg and 1500 mg as single or multiple dose administration under fasted or fed conditions. The PK model was developed stepwise: first, the structural and the stochastic model were developed. Secondly, a covariate analysis was performed. Parameter estimation and simulations were performed using non-linear-mixed-effects methods implemented in the software NONMEM (version 7.3.0).
Results: The dataset included 5644 plasma and 316 urinary concentrations of metformin from 175 healthy subjects. 32 volunteers received multiple doses of IR and 143 of ER formulation. The PK profile of metformin in healthy volunteers was best described by a two-compartment disposition model following flip-flop kinetics, which is already described in literature [2] (first-order absorption rate constant 0.30 h-1; first-order elimination rate constant 1.07 h-1). To describe the PK of the ER formulation, a zero-order infusion into the absorption compartment was implemented with a duration of 2.34 h in fasted volunteers and increased under fed conditions to 4.00 h. The bioavailability was estimated as 27.7% using the total amount recovered in the urine. As metformin is not metabolized and fully cleared by the kidneys [3] this amount reflects the fraction absorbed and therewith the absolute bioavailability. The ER formulation has a 1.15-fold higher bioavailability compared to the IR formulation. Fed state increases the bioavailability by a factor of 1.67. The volumes of distribution were 30.0 l for central and 196 l for the peripheral compartment.
Conclusions: Metformin blood concentrations as well as urinary concentrations were accurately quantified by a two-compartment model. Food-intake, different formulations and administration regimen were implemented as covariates.
References:
[1] Inzucchi SE et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a position statement of the american diabetes association and the european association for the study of diabetes. Diabetes Care. 2015;38(1):140–9.
[2] Pentikäinen PJ et al. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol. 1979;16(3):195–202.
[3] Graham GG et al. Clinical Pharmacokinetics of Metf ormin. Clin Pharmacokinet. 2011;50(2):81–98.