Pharmacokinetic Properties of Dapagliflozin in Patients with Stage 4 Chronic Kidney Disease.

Introduction: The pharmacokinetic data on dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, are limited in patients with severe renal impairment. We aimed to evaluate the pharmacokinetic properties and safety of dapagliflozin in patients with chronic kidney disease (CKD) stage 4.

Methods: This was a single-center, open-label, pharmacokinetic trial involving single, and multiple doses. Patients with an estimated glomerular filtration rate (eGFR) of 15-<30 mL/min/1.73 m2 were enrolled. The single-dose group received 10 mg of oral dapagliflozin once daily, while the multiple-dose group received 10 mg daily for 5 days. Pharmacokinetic parameters, pharmacodynamic response, and tolerability were assessed.

Results: A total of 12 participants completed the single-dose study, and 9 participants completed the multiple-dose study. The mean eGFR was 23.4 and 23.2 mL/min/1.73 m2 in single- and multiple-dose group, respectively. In the single-dose group, dapagliflozin was rapidly absorbed and metabolized to produce dapagliflozin 3-O-glucuronide (D3OG), with a mean Tmax of 0.7 h and 1.8 h, and a mean T1/2 of 16.7 h and 14.9 h, respectively. Participants with an eGFR of 15-24 mL/min/1.73 m2 exhibited higher AUC0-∞ and mean residence time for D3OG compared to those with an eGFR of 25-30 mL/min/1.73 m2. In the multiple-dose group, there was no significant accumulation of dapagliflozin, as indicated by the ratio of AUCTau (918.6 ± 155.2 h × ng/mL) to AUC0-24 h (917.1 ± 154.7 h × ng/mL) was close to 1. In the multiple-dose group, urinary albumin/creatinine ratio decreased by 21% and 24-h urinary protein decreased by 23% from baseline to 24 h after the last dose.

Conclusion: In conclusion, no clinically significant accumulation of dapagliflozin was observed in patients with stage 4 CKD.