PMID- 25659911 OWN - NLM STAT- MEDLINE DCOM- 20160329 LR - 20181202 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 37 IP - 3 DP - 2015 Mar 1 TI - Effect of hepatic or renal impairment on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor. PG - 610-628.e4 LID - S0149-2918(14)00871-6 [pii] LID - 10.1016/j.clinthera.2014.12.013 [doi] AB - PURPOSE: Canagliflozin is a sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). Because T2DM is often associated with renal or hepatic impairment, understanding the effects of these comorbid conditions on the pharmacokinetics of canagliflozin, and further assessing its safety, in these special populations is essential. Two open-label studies evaluated the pharmacokinetics, pharmacodynamics (renal study only), and safety of canagliflozin in participants with hepatic or renal impairment. METHODS: Participants in the hepatic study (8 in each group) were categorized based on their Child-Pugh score (normal hepatic function, mild impairment [Child-Pugh score of 5 or 6], and moderate impairment [Child-Pugh score of 7-9]) and received a single oral dose of canagliflozin 300 mg. Participants in the renal study (8 in each group) were categorized based on their creatinine clearance (CLCR) (normal renal function [CLCR >/=80 mL/min]; mild [CLCR 50 to <80 mL/min], moderate [CLCR 30 to <50 mL/min], or severe [CLCR <30 mL/min] renal impairment; and end-stage renal disease [ESRD]) and received a single oral dose of canagliflozin 200 mg; the exception was those with ESRD, who received 1 dose postdialysis and 1 dose predialysis (10 days later). Canagliflozin's pharmacokinetics and pharmacodynamics (urinary glucose excretion [UGE] and renal threshold for glucose excretion [RTG]) were assessed at predetermined time points. FINDINGS: Mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinite (AUC)0-infinity values differed by <11% between the group with normal hepatic function and those with mild and moderate hepatic impairment. In the renal study, the mean Cmax values were 13%, 29%, and 29% higher and the mean AUC0-infinity values were 17%, 63%, and 50% higher in participants with mild, moderate, and severe renal impairment, respectively; values were similar in the ESRD group relative to the group with normal function, however. The amount of UGE declined as renal function decreased, whereas RTG was not suppressed to the same extent in the moderate to severe renal impairment groups (mean RTG, 93-97 mg/dL) compared with the mild impairment and normal function groups (mean RTG, 68-77 mg/dL). IMPLICATIONS: Canagliflozin's pharmacokinetics were not affected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin increased in the renal impairment groups relative to participants with normal renal function. Pharmacodynamic response to canagliflozin, measured by using UGE and RTG, declined with increasing severity of renal impairment. A single oral dose of canagliflozin was well tolerated by participants in both studies. ClinicalTrials.gov identifiers: NCT01186588 and NCT01759576. CI - Copyright (c) 2015 Elsevier HS Journals, Inc. All rights reserved. FAU - Devineni, Damayanthi AU - Devineni D AD - Janssen Research & Development, LLC, Raritan, New Jersey. Electronic address: ddevinen@its.jnj.com. FAU - Curtin, Christopher R AU - Curtin CR AD - Janssen Research & Development, LLC, Raritan, New Jersey. FAU - Marbury, Thomas C AU - Marbury TC AD - Orlando Clinical Research Center, Orlando, Florida. FAU - Smith, William AU - Smith W AD - New Orleans Center for Clinical Research, The University of Tennessee Medical Center, Knoxville, Tennessee. FAU - Vaccaro, Nicole AU - Vaccaro N AD - Janssen Research & Development, LLC, San Diego, California. FAU - Wexler, David AU - Wexler D AD - Janssen Research & Development, LLC, San Diego, California. FAU - Vandebosch, An AU - Vandebosch A AD - Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium. FAU - Rusch, Sarah AU - Rusch S AD - Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium. FAU - Stieltjes, Hans AU - Stieltjes H AD - Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium. FAU - Wajs, Ewa AU - Wajs E AD - Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium. LA - eng SI - ClinicalTrials.gov/NCT01186588 SI - ClinicalTrials.gov/NCT01759576 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150203 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0SAC974Z85 (Canagliflozin) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Adult MH - Aged MH - Area Under Curve MH - Canagliflozin/*pharmacokinetics MH - Diabetes Mellitus, Type 2/*drug therapy MH - Female MH - Glucose/metabolism MH - Humans MH - Kidney Failure, Chronic/complications MH - Liver Diseases/*complications MH - Male MH - Middle Aged MH - Renal Insufficiency/*complications MH - Sodium-Glucose Transporter 2 Inhibitors OTO - NOTNLM OT - ESRD OT - T2DM OT - canagliflozin OT - hepatic impairment OT - pharmacokinetics OT - renal impairment EDAT- 2015/02/11 06:00 MHDA- 2016/03/30 06:00 CRDT- 2015/02/10 06:00 PHST- 2014/09/18 00:00 [received] PHST- 2014/12/03 00:00 [revised] PHST- 2014/12/17 00:00 [accepted] PHST- 2015/02/10 06:00 [entrez] PHST- 2015/02/11 06:00 [pubmed] PHST- 2016/03/30 06:00 [medline] AID - S0149-2918(14)00871-6 [pii] AID - 10.1016/j.clinthera.2014.12.013 [doi] PST - ppublish SO - Clin Ther. 2015 Mar 1;37(3):610-628.e4. doi: 10.1016/j.clinthera.2014.12.013. Epub 2015 Feb 3.