Interindividual variability in metformin pharmacokinetics in pediatric patients

Background Metformin is the first-line treatment for type 2 diabetes mellitus in pediatric patients and it's prescriptions in children have increased for off-label indications. However, interindividual variability of metformin pharmacokinetics in children is not well studied. Metformin is a cation that requires multiple transporters for its absorption, distribution and elimination, including organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) transporters. Methods We conducted a 12 h clinical pharmacokinetic study in 36 pediatric patients (age, 7-21 years) treated with metformin and analyzed the data using non-compartmental and population pharmacokinetic models to describe metformin pharmacokinetics and associated covariates. The association of OCT and MATE genetic variants on metformin absorption and elimination was investigated. Results The dose-normalized plasma exposure of metformin varied by 3.3-fold among children. Renal clearance was higher in children compared to the reported data in healthy adults or adults with diabetes. Total body weight (TBW) and estimated glomerular filtration rate (eGFR) significantly affected metformin oral clearance. OCT2 c.390 G > T (p.Thr130 = , rs624249) was associated with metformin oral clearance and secretary clearance, whereas OCT3 c.-29G > A (rs555754) and c.360 C > T (p.Arg120 = , rs668871) were significantly associated with the absorption rate constant and oral clearance. Conclusion Metformin dosing in children can be optimized based on TBW, eGFR, and OCT2/3 genetic variants to improve its safety and efficacy. Impact Metformin pharmacokinetics is highly variable, and limited data are available on the pediatric population. Total body weight and estimated glomerular filtration rate are associated with metformin oral clearance. OCT2/3 genetic variants can influence the elimination and absorption of metformin. Consideration of population factors associated with metformin pharmacokinetics in dose selection can improve its safety and efficacy.