#558 Population pharmacokinetic modelling of canagliflozin in advanced chronic kidney disease
Bibliographic record
Abstract
Abstract Background and Aims 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) and renal outcomes [1–3]. Its initiation is currently not recommended in advanced CKD (eGFR <30 ml/min/1.73 m²), end-stage kidney disease, or in those on kidney replacement therapies due to insufficient clinical and safety data [4]. 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. Method PK data were obtained from a single-center, prospective, single-arm, open-label interventional study conducted in two cohorts. The first cohort involved detailed PK sampling in 10 patients receiving intermittent HD, while the second included sparse PK sampling in 13 patients with CKD stage 4 or 5 not yet on dialysis [5]. A total of 332 PK observations from 23 patients were analyzed. 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). Results 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 (Ka), which increased with age. Sex was a significant covariate for the apparent volume of distribution (V/F), which was lower in females (80.7 L in males and 49.1 L in females). The steady-state area under the curve (AUC) was higher in older patients and females, especially at the 300 mg dose. No difference in steady-state exposures was observed between patients with advanced CKD and those undergoing hemodialysis. Conclusion The developed model effectively characterizes the pharmacokinetics of canagliflozin in patients with advanced CKD, including those undergoing hemodialysis. The study demonstrates that steady state canagliflozin exposure is higher in older patients and females, particularly at the 300 mg dose, while renal function was not a significant determinant of exposure in advanced CKD patients.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".