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 (AUC _0–24h). 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 AUC _0–24h was calculated using the equation AUC _0–24h = 4.779 * C ₃ + 13.174 * C ₁₀. 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) AUC _{0 − 24h}, CL _renal, C ₃ and C ₁₀, 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. GFR _i was correlated with metformin AUC and CL _renal (P <.001). As expected, we found a great pharmacokinetic interindividual variability among the volunteers and no effect of the OCT1 genotype on the AUC _{0 − 24h}. We were unable to reproduce our previous finding of a gene–gene interaction (OCT2 and MATE1) effect on CL _renal in this cohort. Conclusion: This study further supports the use of the 2-point LSS algorithm in large pharmacokinetic trials.