The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus

Abstract

Aim(s): This study assessed the effect of differences in renal function on the pharmacokinetics and pharmacodynamics of dapagliflozin, a renal sodium glucose co-transporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus (T2DM).

Methods: A single 50 mg dose of dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups: healthy non-diabetic subjects; patients with T2DM and normal kidney function and patients with T2DM and mild, moderate or severe renal impairment based on estimated creatinine clearance. Subsequently, 20 mg once daily multiple doses of dapagliflozin were evaluated in the patients with T2DM. Formation rates of dapagliflozin 3-O-glucuronide (D3OG), an inactive metabolite, were evaluated using human isolated kidney and liver microsomes.

Results: Plasma concentrations of dapagliflozin and D3OG were incrementally increased with declining kidney function. Steady-state Cmax for dapagliflozin were 4%, 6% and 9% higher and for D3OG were 20%, 37% and 52% higher in patients with mild, moderate and severe renal impairment, respectively, compared with normal function. AUC(0,τ) was likewise higher. D3OG formation in kidney microsomes was three-fold higher than in liver microsomes and 109-fold higher than in intestine microsomes. Compared with patients with normal renal function, pharmacodynamic effects were attenuated with renal impairment. Steady-state renal glucose clearance was reduced by 42%, 83% and 84% in patients with mild, moderate or severe renal impairment, respectively.

Conclusions: These results indicate that both kidney and liver significantly contribute to dapagliflozin metabolism, resulting in higher systemic exposure with declining kidney function. Dapagliflozin pharmacodynamics in diabetic subjects with moderate to severe renal impairment are consistent with the observation of reduced efficacy in this patient population.

Keywords: UGT1A9; dapagliflozin; glucuronosyltransferase; renal insufficiency; sodium-glucose transporter 2; type 2 diabetes mellitus.

© 2012 Bristol-Myers Squibb Co. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Figures

Figure 1

Plasma concentration vs. time curves for (A) dapagliflozin and (B) D3OG after seven 20 mg day−1 doses of dapagliflozin (steady-state, day 10) in subjects with T2DM and varying degrees of kidney function. D3OG, dapagliflozin 3-O-glucuronide; T2DM, type 2 diabetes mellitus. , T2DM patients with normal kidney function; , T2DM patients with mild renal impairment; , T2DM patients with moderate renal impairment; , T2DM patients with severe renal impairment

Figure 2

Linear regression analyses for AUC(0,τ) of (A) dapagliflozin and (B) D3OG on total iohexol systemic clearance after seven 20 mg day−1 doses of dapagliflozin (steady-state, day 10) in subjects with T2DM and varying degrees of kidney function. D3OG, dapagliflozin 3-O-glucuronide; T2DM, type 2 diabetes mellitus. , T2DM patients with normal kidney function; , T2DM patients with mild renal impairment; , T2DM patients with moderate renal impairment; , T2DM patients with severe renal impairment

Figure 3

Formation rates of (A) D3OG and (B) D2OG after incubation of dapagliflozin with human kidney, liver or intestine microsomes at a protein concentration of 0.25 mg ml−1 in the presence of uridine 5′-diphosphoglucuronic acid. D2OG, dapagliflozin 2-O-glucuronide; D3OG, dapagliflozin 3-O-glucuronide; T2DM, type 2 diabetes mellitus. , human liver microsomes; , human kidney microsomes; , human intestine microsomes

Figure 4

Effect of dapagliflozin on mean (+SD) fasting renal glucose clearance (0–6 h) at baseline (day −1) and after a single 50 mg dose (day 1), the first 20 mg day−1 dose (day 4) and the seventh 20 mg day−1 dose (steady-state, day 10). DAPA, dapagliflozin; T2DM, type 2 diabetes mellitus. , healthy subjects with normal kidney function; , T2DM patients with normal kidney function; , T2DM patients with mild renal impairment; , T2DM patients with moderate renal impairment; , T2DM patients with severe renal impairment

Figure 5

Scatter plot and fitted regression line of renal glucose clearance vs. urinary CLcr for (A) a single dose of 50 mg (day 1) and (B) the seventh 20 mg day−1 dose (steady-state, day 10) of dapagliflozin. CLcr, creatinine clearance; T2DM, type 2 diabetes mellitus. , healthy subjects with normal kidney function; , T2DM patients with normal kidney function; , T2DM patients with mild renal impairment; , T2DM patients with moderate renal impairment; , T2DM patients with severe renal impairment