LBODP083 Pharmacokinetics Of Metformin In Obese Non-diabetic Youth: Drug Clearance Increases With Severity Of Obesity

Abstract

Abstract Background Severe obesity and obesity-related conditions, such as prediabetes, are increasing in prevalence among pediatric populations. Metformin is an oral biguanide that is often used off label to treat obesity and prediabetes in youth. Despite increased prescribing in youth, there is limited knowledge about pharmacokinetics (PK) of metformin in pediatric populations, and no published data describing the effect of obesity severity on metformin PK. Research Questions What is the variability of pharmacokinetic properties of immediate release metformin in obese, non-diabetic adolescents? Does severity of obesity impact these properties? Methodology Youth 12-17 years of age were included if they were obese with laboratory evidence of insulin resistance (HOMA-IR > 3) or met ADA criteria for prediabetes and had a normal renal function (GFR > 60 mL/min/1.73m2). Obesity classes were defined as class I (BMI > 95th to < 120% of the 95th percentile), class II (> 120% to < 140% of the 95th percentile), and class III (> 140% of the 95th percentile). Youth were treated with immediate release metformin dosed twice daily for at least 6 weeks. Pill diaries and pill counts were conducted to assess adherence. Youth arrived fasting and received their AM dose of metformin with a standardized meal. Blood was drawn pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose and urine collected throughout the visit. Primary outcomes included the mean, standard deviation, and range for steady state area under the plasma drug concentration-time curve adjusted for dose (AUCss_D) and apparent oral clearance at steady state (CLss/F). These outcomes were compared between obesity classes. MAJOR RESULTS There were 11 subjects (10 females), mean (SD) age was 14.3 (1.8) years. Metformin doses included: 1000mg BID (N=8), 500mg qAM 1000mg qPM (N=2), 500mg BID (N=1). Mean (SD) weight was 102.8 (19.2) kg, and mean BMI 37.5 (3.3) kg/m2. Among participants, there were N=4 with class III obesity, N=4 with class II obesity, and N=3 with class I obesity. Across all study participants, mean AUCss _D was 12.5 (SD 2.46; range 8.48-16.9) h*ng/mL/mg and mean CLss/F was 85.7 (SD 16.6; range 59. 0-118) L/h. Mean CLss/F was 76.8, 83.6, and 86.2 L/h in class I, II, and III obesity, respectively. Mean AUCss _D was 13.5, 12.17, 12.14 h*ng/mL/mg in class I, II, and III obesity, respectively. No differences were statistically significant. Conclusions Our pilot data suggest a 2-fold variability in apparent clearance among study participants, with apparent clearance increasing in relation to obesity severity class. Greater clearance, and thus reduced systemic exposure (AUC), may indicate a need for a larger dose of metformin in severely obese youth. Additional data is needed to further evaluate the impact of the severity of obesity on metformin clearance. Presentation: No date and time listed