Population Pharmacokinetic Modeling of Canagliflozin in Advanced Chronic Kidney Disease.

Abstract

Background and objectives: Canagliflozin is an orally active, selective, reversible sodium-glucose cotransport-2 (SGLT-2) inhibitor used in patients with chronic kidney disease (CKD) to prevent cardiovascular (CV) events and CKD progression. Its initiation is currently not recommended in advanced CKD [estimated glomerular filtration rate (eGFR) < 20 mL/min per 1.73 m²], end-stage kidney disease, or in those on kidney replacement therapies due to insufficient clinical and safety data. This study aimed to develop a population pharmacokinetic (popPK) model using data from patients with advanced CKD, including those on maintenance hemodialysis (HD), to characterize the steady-state pharmacokinetics (PK) of canagliflozin at 100 mg and 300 mg doses, and to assess the impact of significant covariates on its PK.

Methods: PK data were obtained from a single-center, prospective, single-arm, open-label interventional study conducted in two cohorts. The first cohort was a detailed PK sampling done in 10 patients receiving intermittent HD for at least 3 months and the second cohort included sparse PK sampling in 13 patients with advanced CKD, not yet on dialysis. Canagliflozin PK parameters were modeled using nonlinear mixed-effects modeling (NONMEM^® version 7.5) with the first-order conditional estimation method with interaction. Model performance was evaluated using goodness of fit plot, bootstrap (n = 1000), and normalized prediction distribution error (NPDE). Model-based simulations were performed using the final model to predict concentration-time profiles at steady state, evaluate the impact of significant covariates on predicted steady-state area under the curve (AUC), and compare PK profiles between patients with non-dialysis CKD and those with hemodialysis.

Results: A total of 332 PK observations from 23 patients were analyzed. The mean age of the cohort was 67 ± 15 years with a mean body mass index of 27 ± 5 kg/m². A two-compartment popPK model of canagliflozin with lag-time, sequential zero- and first-order absorption, and first-order elimination was developed. Age was a significant covariate of the absorption rate constant (K_a), which increased with age. Sex was a significant covariate for the apparent volume of distribution (V/F), which was lower in women (80.7 L in men and 49.1 L in women). Model-based simulations demonstrated that steady-state AUC was 66% higher in women compared with men. Additionally, AUC increased approximately threefold in both sexes when the canagliflozin dose was escalated from 100 mg to 300 mg. Notably, eGFR was not a determinant of steady state exposure.

Conclusions: The developed model demonstrates that steady state canagliflozin exposure is higher in women and with use of higher dose, whereas eGFR does not meaningfully alter drug exposure in patients with advanced CKD. Model-based simulations support the potential use of canagliflozin in HD patients and highlight the need for further evaluation of dose optimization strategies in this high-risk population.

Trial registration: The trials were registered at Clinicaltrials.gov (NCT05309785).