Elenjickal Elias John, Mavrakanas Thomas A, Gritsas Ari, Suri Rita S, Marsot Amélie
Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Clin Pharmacokinet. 2025 Sep 15. doi: 10.1007/s40262-025-01571-8.
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 m], 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.
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.
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/m. 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), 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.
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.
The trials were registered at Clinicaltrials.gov (NCT05309785).
卡格列净是一种口服活性、选择性、可逆的钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂，用于慢性肾脏病（CKD）患者以预防心血管（CV）事件和CKD进展。目前，对于晚期CKD[估计肾小球滤过率（eGFR）<20 mL/（min·1.73 m²）]、终末期肾病患者或接受肾脏替代治疗的患者，由于临床和安全性数据不足，不建议起始使用该药物。本研究旨在利用晚期CKD患者（包括维持性血液透析（HD）患者）的数据建立群体药代动力学（popPK）模型，以表征100 mg和300 mg剂量卡格列净的稳态药代动力学（PK），并评估显著协变量对其PK的影响。
PK数据来自一项在两个队列中进行的单中心、前瞻性、单臂、开放标签干预研究。第一个队列是对10例接受间歇性HD至少3个月的患者进行详细的PK采样，第二个队列包括对13例尚未接受透析的晚期CKD患者进行稀疏PK采样。使用非线性混合效应模型（NONMEM 7.5版）和带有交互作用的一阶条件估计法对卡格列净的PK参数进行建模。使用拟合优度图、自抽样法（n = 1000）和标准化预测分布误差（NPDE）评估模型性能。使用最终模型进行基于模型的模拟，以预测稳态下的浓度-时间曲线，评估显著协变量对预测的稳态曲线下面积（AUC）的影响，并比较非透析CKD患者和血液透析患者的PK曲线。
共分析了来自23例患者的332个PK观测值。该队列的平均年龄为67±15岁，平均体重指数为27±5 kg/m²。建立了一个具有滞后时间、连续零级和一级吸收以及一级消除的卡格列净二室popPK模型。年龄是吸收速率常数（K）的显著协变量，其随年龄增加。性别是表观分布容积（V/F）的显著协变量，女性的V/F较低（男性为80.7 L，女性为49.1 L）。基于模型的模拟表明，女性的稳态AUC比男性高66%。此外，当卡格列净剂量从100 mg增加到300 mg时，两性的AUC均增加约三倍。值得注意的是，eGFR不是稳态暴露的决定因素。
所建立的模型表明，女性和使用较高剂量时卡格列净的稳态暴露较高，而eGFR在晚期CKD患者中不会显著改变药物暴露。基于模型的模拟支持卡格列净在HD患者中的潜在应用，并强调需要在这一高危人群中进一步评估剂量优化策略。
这些试验已在Clinicaltrials.gov上注册（NCT05309785）。
