Population pharmacokinetics and pharmacodynamics of canagliflozin in paediatric patients with type 2 diabetes mellitus
Nele Goeyvaerts, Per Olsson Gisleskog, Martine Neyens, Juan José Perez Ruixo, Saberi Rana Ali, Iolanda Cirillo, Oliver AckaertAbstract
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
Estimated and simulated steady‐state area under the concentration–time curve during 24 h (AUC 24h ) and maximum drug concentration were comparable between paediatric patients and adults for canagliflozin 100‐ or 300‐mg QD. Simulated steady‐state AUC 24h 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.