Using a limited sampling strategy to investigate the interindividual pharmacokinetic variability in metformin: A large prospective trial

Aims Recently a limited sampling strategy (LSS) for determination of metformin' pharmacokinetics was developed. The LSS utilizes the plasma concentration of metformin 3 and 10 hours after oral intake of a single dose to estimate the area under the concentration–time curve up to 24 hours (AUC0–24h). The main purpose of this study was to support the feasibility of this strategy in a large prospective trial. Methods Volunteers orally ingested two 500‐mg tablets of metformin hydrochloride. A blood sample was drawn three and ten hours after the ingestion. Urine was collected for 0–10 and 10–24 hours and urine volumes recorded. The AUC0–24h was calculated using the equation AUC0–24h = 4.779 * C3 + 13.174 * C10. Additionally, all participants were genotyped for the single‐nucleotide polymorphism A270S in OCT2, g.‐66 T > C in MATE1, R61C, G465R, G401S and the deletion M420del in OCT1. Results In total, 212 healthy volunteers participated. The median (25th ‐ 75th interquartile range) AUC0 − 24h, CLrenal, C3 and C10, were 10 600 (8470–12 500) ng* hr* mL−1, 29 (24–34) L* hour−1, 1460 (1180–1770) and 260 (200–330) ng* mL−1, respectively, which is in agreement with our previous results. GFRi was correlated with metformin AUC and CLrenal (P < .001). As expected, we found a great pharmacokinetic interindividual variability among the volunteers and no effect of the OCT1 genotype on the AUC0 − 24h. We were unable to reproduce our previous finding of a gene–gene interaction (OCT2 and MATE1) effect on CLrenal in this cohort. Conclusion This study further supports the use of the 2‐point LSS algorithm in large pharmacokinetic trials.