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

Abstract

Introduction: The pharmacokinetic data on dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is 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/1.73m2 were enrolled. The single-dose group received 10mg of oral dapagliflozin once daily, while the multiple-dose group received 10mg daily for five 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/1.73m2 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 hours and 1.8 hours, and a mean T1/2 of 16.7 hours and 14.9 hours, respectively. Participants with an eGFR of 15-24 mL/min/1.73m2 exhibited higher AUC0-∞ and mean residence time (MRT) for D3OG compared to those with an eGFR of 25-30 mL/min/1.73m2. 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 AUC0-24h (917.1 ± 154.7 h×ng/mL) was close to 1. In the multiple-dose group, UACR decreased by 21% and 24-hour urinary protein decreased by 23% from baseline to 24 hours after the last dose.

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