Populations simulations (n=500) of metformin plasma concentration in children with obesity based on the current recommended maximum dose of 2,000 mg/d (A) and the newly proposed maximum of 3,000 mg/d (B-C). Simulations reflect steady state concentrations over the last 24 h following 1,000 mg twice daily (A), 1,000 mg three times per day (B), and 1,500 mg twice daily (C). The virtual population includes children with BMI >95th percentile. The shaded regions represent the 90% model prediction interval, and the dashed line represents the median simulated concentration. The dashed horizontal line represents 5 mg/L, the plasma concentration threshold associated with lactic acidosis.4