Obesity is associated with increased clearance and reduced drug exposure to metformin in youth with type 2 diabetes

Objective: Youth with type 2 diabetes (T2D) have higher metformin treatment failure rates when compared with adults. Our objectives were to develop a population pharmacokinetic (PK) model for metformin in youth to examine current dosing strategies and to quantify the relationship between metformin PK and obesity in youth with T2D. Research Design and Methods: We performed semi intensive PK sampling in 50 youth < 18 years with T2D on metformin. We measured metformin levels before, 1 to 2 and 3 to 6 hours after a supervised 1000 mg dose of immediate release metformin. We used non linear mixed effects modeling to develop a population PK model. Simulations were performed to estimate area under the 24 hour metformin concentration time curve (AUC) values. Results: Mean age was 15.0 (SD 1.6) y, 66% were male, mean body mass index (BMI), 35.9 (SD 6.8) kg/m2, and mean eGFR, 114.7 (SD 22.6) mL/min/1.73m2. Estimated CL increased by 3% (21.4% CV) for every 1 kg/m2 increase in BMI, and by 6% (53.8% CV) for every 10 mL/min increase in eGFR. When comparing AUC estimates from our model with data from 236 adults on metformin, median AUC for youth was lower than for adults on 2000 mg of metformin (18.47 mg*h/L vs. 27.49 mg*h/L). Simulations showed that in youth, higher doses of at least 2,550 mg and up to 3,000 mg daily were needed to achieve exposures similar to adults. Conclusions: Obesity is associated with increased metformin CL and reduced AUC in youth and higher doses are needed to achieve comparable drug exposure to adults.