147-OR: Obesity Is Associated with Increased Clearance and Reduced Drug Exposure to Metformin in Youth with Type 2 Diabetes

Introduction & Objectives: Youth have higher treatment failure rates on metformin when compared with adults. There is interpatient variability in metformin pharmacokinetics (PK) and the influence of obesity on metformin PK in youth remains unclear. Our objectives were to develop a population 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.

Methods: We performed semi-intensive PK sampling in 50 youth < 18 years with T2D on metformin. We measured metformin levels before, 1-2 and 3-6-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 participant age was 15.0 (SD 1.6) years, 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. A one-compartment model best described the data, with the following parameter estimates: clearance (CL), 110 L/h (7.8% CV); volume of distribution, 461 L (11.0% CV); absorption rate constant, 0.76 /h (9.8% CV). 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 those from a model developed using data from 236 adults on metformin, median AUC for youth receiving 2000 mg metformin daily was lower than for adults on the same dose (18.47 mg*h/L vs. 27.49 mg*h/L). Simulations showed that in youth, higher doses of at least 2550 mg and up to 3000 mg daily were needed to achieve exposures similar to adults.

Conclusion: Obesity is associated with increased metformin CL and reduced AUC in youth and higher doses are needed to achieve comparable drug exposure to adults. As next steps, we are testing the tolerability and efficacy of higher doses of metformin in a clinical trial.