Population pharmacokinetics and pharmacodynamics of canagliflozin in paediatric patients with type 2 diabetes mellitus

AIMS: Canagliflozin was recently approved in type 2 diabetes mellitus (T2DM) patients ≥10 and <18 years old as a single agent dosed once daily (QD) or in a fixed-dose combination with metformin dosed twice daily (BID). We characterize canagliflozin pharmacokinetics in paediatric patients with T2DM, compare estimated individual and simulated exposure metrics for QD and BID doses in paediatric patients and adults, and investigate the relationship between canagliflozin plasma concentrations and change from baseline HbA1c with QD and BID doses. METHODS: Paediatric population pharmacokinetics and pharmacokinetics/pharmacodynamics models were based on the previously developed corresponding adult models, using Phase 1 and 3 study data, evaluating canagliflozin 100- or 300-mg QD doses in paediatric patients with T2DM. Modelling encompassed exploratory analysis, external evaluation, model update and simulation of canagliflozin exposure metrics and HbA1c for QD and BID doses. RESULTS: was similar between QD and BID dosing for the same canagliflozin total daily dose in paediatric patients and adults with T2DM. QD to BID bridging was supported by simulated HbA1c and change from baseline in HbA1c in paediatric patients. CONCLUSIONS: No canagliflozin dose adjustments are required alone or in combination with metformin to ensure similar plasma exposures between paediatric and adult patients with T2DM, as well as similar HbA1c lowering between QD and BID dosing in paediatric patients.