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The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus.
Br J Clin Pharmacol. 2013 Sep; 76(3):432-44.BJ

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.

Authors+Show Affiliations

Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Co, Princeton, NJ.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23210765

Citation

Kasichayanula, Sreeneeranj, et al. "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, vol. 76, no. 3, 2013, pp. 432-44.
Kasichayanula S, Liu X, Pe Benito M, et al. The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol. 2013;76(3):432-44.
Kasichayanula, S., Liu, X., Pe Benito, M., Yao, M., Pfister, M., LaCreta, F. P., Humphreys, W. G., & 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(3), 432-44. https://doi.org/10.1111/bcp.12056
Kasichayanula S, et al. The Influence of Kidney Function On Dapagliflozin Exposure, Metabolism and Pharmacodynamics in Healthy Subjects and in Patients With Type 2 Diabetes Mellitus. Br J Clin Pharmacol. 2013;76(3):432-44. PubMed PMID: 23210765.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. AU - Kasichayanula,Sreeneeranj, AU - Liu,Xiaoni, AU - Pe Benito,Melanie, AU - Yao,Ming, AU - Pfister,Marc, AU - LaCreta,Frank P, AU - Humphreys,William Griffith, AU - Boulton,David W, PY - 2012/09/14/received PY - 2012/11/25/accepted PY - 2012/12/6/entrez PY - 2012/12/6/pubmed PY - 2014/5/3/medline KW - UGT1A9 KW - dapagliflozin KW - glucuronosyltransferase KW - renal insufficiency KW - sodium-glucose transporter 2 KW - type 2 diabetes mellitus SP - 432 EP - 44 JF - British journal of clinical pharmacology JO - Br J Clin Pharmacol VL - 76 IS - 3 N2 - 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. SN - 1365-2125 UR - https://www.unboundmedicine.com/medline/citation/23210765/The_influence_of_kidney_function_on_dapagliflozin_exposure_metabolism_and_pharmacodynamics_in_healthy_subjects_and_in_patients_with_type_2_diabetes_mellitus_ L2 - https://doi.org/10.1111/bcp.12056 DB - PRIME DP - Unbound Medicine ER -