Inès-Gynette Buzirukanyo(1), Jean-Daniel Lalau(2,3), Maria C. Kjellsson(1)
(1) Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden (2) Service d'Endocrinologie‐Nutrition, Hôpital Sud, Amiens, France (3) Unité INSERM 1088, Université de Picardie Jules Verne, Amiens, France
Introduction: Kajbaf et al [1] investigated the pharmacokinetics (PK) of metformin in people with supratherapeutic metformin concentrations (≥ 5 mg/L), determining both plasma and erythrocyte concentrations. They found that the half-life of metformin was unexpectedly long in this group. Participants in the Kajbaf-study, all had impaired renal function and supratherapeutic concentrations of metformin. Analysing the data using non-compartmental analysis did not account for non-linearity in metformin PK and the relative importance of renal impairment versus level of supratherapeutic concentrations was inconclusive. Stage et al [2] published a population PK model of metformin in which parameters of disposition and elimination were expressed as independent of bioavailability, taking into account measurements of creatinine clearance (CLCR) as a covariate on clearance. The objective of this study was to re-used the population PK model developed by Stage et al [2] to investigated the impact of renal function and supratherapeutic concentration on the duration until therapeutic concentrations (< 5 mg/L), taking non-linearity of metformin PK into account.
Methods: Two data sources were used: the data used by Stage et al [2]to develop the published PK model and the data produced in the study by Kajbaf et al [1]. Metformin concentrations (plasma and urine) in the Stage-studies came from single and repeated dosing of metformin in healthy subjects with therapeutic concentrations (< 4 mg/L) and normal to mildly impaired renal function (CLCR ≥ 70 mL/min). Metformin concentrations (plasma and erythrocyte) from the Kajbaf-study, came from clinical overdose cases with supratherapeutic concentrations, mean [range] 39.9 mg/L [6.0-88 mg/L] and mildly to severely impaired kidney function, mean CLCR [range] 14.9 mL/min [4.8-68 mL/min]. Erythrocyte PK was added to the model by Stage et al [2] and parameters were re-estimates using the full data set. Differences in pharmacokinetics were investigated, assess non-linearity in disposition and elimination. Simulations from the final model were performed with a range of supratherapeutic concentrations (10 mg/L to 100 mg/L by steps of 10 mg/L) and a range of renal function (120 mL/min to 30 mL/min by steps of 10 mL/min) assessing the duration of supratherapeutic concentrations.
Results: Non-linear disposition of metformin into and out of erythrocytes was the only identified difference in PK between the two study groups.The duration of supratherapeutic concentrations, of two people with the same starting concentration, but different CLCR (120 mL/min versus 30 mL/min), was about 20 hours longer for an individual with severe renal impairment relative (90 hours) to normal renal function (69 hours) at starting concentrations of 100 mg/L. The diffence decreased by 30 minutes for each 10 mg/L-reduction of starting concentration in the range 30-100 mg/L. This was a consequence of the saturation of transport out of erythrocytes, leading to a distribution-limited elimination. In contrast, the duration reduced by 13 hours between starting concentration 30 and 20 mg/L, putting the individual with severely impaired renal function at risk for much longer (24.5 h) than the individual with normal renal function (8.5 h).
Conclusion: The time until therapeutic concentrations is linearly related to the magnitude of the metformin concentrations and only when concentrations are close to normal will the renal function have an influence on the duration.
References:
[1] Kajbaf F, Bennis Y, Hurtel-Lemaire AS, Andréjak M, Lalau JD. Unexpectedly long half-life of metformin elimination in cases of metformin accumulation. Diabet Med. 2016; 33: 105-110.
[2] Stage TB, Wellhagen G, VHristensen MMH, Guiastrennec B, Brøsen K, Kjellsson MC. Using a semi-mechanistic model to identify the main sources of variability of metformin pharmacokinetics. Basic Clin Pharmacol Toxicol. 2019; 124: 105-114.
Reference: PAGE () Abstr 9572 [www.page-meeting.org/?abstract=9572]
Poster: Clinical Applications