Nele Goeyvaerts 1, Per Olsson Gisleskog 2, Martine Neyens 1, Juan José Perez Ruixo 3, Saberi Rana Ali 4, Iolanda Cirillo 5, Oliver Ackaert 1
1 Johnson & Johnson (Beerse, Belgium), 2 POG Pharmacometrics (London, United Kingdom), 3 Johnson & Johnson (Madrid, Spain), 4 Johnson & Johnson (Titusville, United States), 5 Johnson & Johnson (Raritan, United States)
Introduction: Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disorder that impacts patients across a broad age range [1, 2]. Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) receptor inhibitor, which increases urinary glucose excretion and is approved worldwide for adults with T2DM as an adjunct to diet and exercise to improve glycaemic control. Recently, canagliflozin was approved in paediatric T2DM patients ≥10 and <18 years of age, supported by data from a phase 1 and phase 3 study showing that canagliflozin was well tolerated and generally safe, and significantly improved glycaemic control compared with placebo. Canagliflozin can be dosed as a single agent (100 mg once daily (QD) starting dose with conditional up-titration to 300 mg QD) or, in the US, as a fixed-dose combination (FDC) with metformin (50 mg twice daily (BID) starting dose with conditional up-titration to 150 mg BID). Objectives: To characterise canagliflozin pharmacokinetics (PK) in paediatric patients with T2DM, to compare estimated individual and simulated exposure metrics for QD and BID doses in paediatric patients and adults, and to investigate the relationship between canagliflozin plasma concentrations and change from baseline in HbA1c with QD and BID doses. Methods: Paediatric population PK (popPK) and PK/pharmacodynamics (PD) models were based on previously developed corresponding adult models [3, 4], using data from the phase 1 and phase 3 studies, both evaluating canagliflozin 100 mg or 300 mg QD doses in paediatric patients with T2DM. The adult popPK model consisted of an open two-compartment disposition model with first-order elimination and a sequential zero-order, first-order absorption after a lag time [3]. The adult PK/PD model consisted of a turnover model for HbA1c with an Emax model for the placebo-corrected HbA1c-lowering effect of canagliflozin included additively on the HbA1c formation rate [4]. Simulations of canagliflozin exposure metrics and HbA1c were generated based on final models for 1,000 female and 1,000 male virtual T2DM patients, accounting for inter-individual and residual variability. NONMEM version 7.4 was used for model fitting and PopPK simulations, while PK/PD simulations were conducted in mrgsolve v1.0.4 in R version 3.6.2. Results: The paediatric canagliflozin popPK model was developed based on 330 plasma PK samples from 90 paediatric patients. In the final paediatric popPK model, parameters were fixed to the estimates of the adult popPK model except for residual error variances, which were re-estimated, and covariate effects of age, eGFR and BMI were removed. Estimated and simulated steady-state exposures were comparable between paediatric patients and adults for canagliflozin 100 mg or 300 mg QD. Simulated area under the concentration-time curve during 24 hours at steady state was similar between QD and BID dosing for the same canagliflozin total daily dose in paediatric and adult patients with T2DM. The paediatric PK/PD model for HbA1c was developed based on 702 HbA1c samples from 160 paediatric patients in the phase 3 study. In the final paediatric PK/PD model, parameters were fixed to estimates from the adult PK/PD model except for the placebo effect, baseline HbA1c and residual error variance, which were re-estimated, and covariate effects of background insulin and treatment group were included. QD to BID bridging for the FDC with metformin was also supported by simulated change from baseline in HbA1c in paediatric patients with T2DM. Conclusions: PopPK and PK/PD modeling and simulation supported that no canagliflozin dose adjustments are required to ensure similar canagliflozin plasma exposures between paediatric and adult patients with T2DM, as well as similar HbA1c lowering between QD dosing and BID dosing (for the FDC with metformin) in paediatric patients. References: [1] Tinajero MG, Malik VS. An Update on the Epidemiology of Type 2 Diabetes: A Global Perspective. Endocrinol Metab Clin North Am. 2021;50:337-355. [2] Kao KT, Sabin MA. Type 2 diabetes mellitus in children and adolescents. Aust Fam Physician. 2016;45:401-406. [3] Hoeben E, De Winter W, Neyens M, et al. Population Pharmacokinetic Modeling of Canagliflozin in Healthy Volunteers and Patients with Type 2 Diabetes Mellitus. Clin Pharmacokinet. 2016;55:209-223. [4] de Winter W, Dunne A, de Trixhe XW, et al. Dynamic population pharmacokinetic-pharmacodynamic modelling and simulation supports similar efficacy in glycosylated haemoglobin response with once or twice-daily dosing of canagliflozin. Br J Clin Pharmacol. 2017;83:1072-1081.
Reference: PAGE 34 (2026) Abstr 12082 [www.page-meeting.org/?abstract=12082]
Poster: Drug/Disease Modelling - Paediatrics