The study was sponsored by Bristol-Myers Squibb Co. and AstraZeneca. All authors were stockholders and/or employees of Bristol-Myers Squibb Co. at the time the study was conducted and analyzed. Dr Pfister is currently an employee of Quantitative Solutions Inc, Menlo Park, CA, USA.
Pharmacokinetic dynamic relationships
The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus
Article first published online: 20 AUG 2013
© 2012 Bristol-Myers Squibb Co. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Special Issue: Cancer Therapeutics Themed Section
Volume 76, Issue 3, pages 432–444, September 2013
How to Cite
Kasichayanula, S., Liu, X., Pe Benito, M., Yao, M., Pfister, M., LaCreta, F. P., Humphreys, W. G. and Boulton, D. W. (2013), The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. British Journal of Clinical Pharmacology, 76: 432–444. doi: 10.1111/bcp.12056
- Issue published online: 20 AUG 2013
- Article first published online: 20 AUG 2013
- Accepted manuscript online: 4 DEC 2012 09:32AM EST
- Manuscript Accepted: 25 NOV 2012
- Manuscript Received: 14 SEP 2012
- Bristol-Myers Squibb Co.
- renal insufficiency;
- sodium-glucose transporter 2;
- type 2 diabetes mellitus;
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).
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.
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.
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.