title: Effect of hepatic or renal impairment on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  Mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinite (AUC)0-∞ 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-∞ 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).
  
  
  CONCLUSIONS
  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.
authors: Janssen Research & Development, LLC, Raritan, New Jersey. Electronic address: ddevinen@its.jnj.com.
authors: Damayanthi
authors: D
authors: Devineni
authors: Janssen Research & Development, LLC, Raritan, New Jersey.
authors: Christopher R
authors: CR
authors: Curtin
authors: Orlando Clinical Research Center, Orlando, Florida.
authors: Thomas C
authors: TC
authors: Marbury
authors: New Orleans Center for Clinical Research, The University of Tennessee Medical Center, Knoxville, Tennessee.
authors: William
authors: W
authors: Smith
authors: Janssen Research & Development, LLC, San Diego, California.
authors: Nicole
authors: N
authors: Vaccaro
authors: Janssen Research & Development, LLC, San Diego, California.
authors: David
authors: D
authors: Wexler
authors: Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors: An
authors: A
authors: Vandebosch
authors: Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors: Sarah
authors: S
authors: Rusch
authors: Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors: Hans
authors: H
authors: Stieltjes
authors: Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors: Ewa
authors: E
authors: Wajs
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D000068896:Canagliflozin / Q000493:pharmacokinetics*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications; D008107:Liver Diseases / Q000150:complications*; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000150:complications*; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin; D005947:Glucose
keywords: ESRD; T2DM; canagliflozin; hepatic impairment; pharmacokinetics; renal impairment