istered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O -glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible.
Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O -glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.
Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.
Specific Populations
Renal Impairment
A single-dose, open-label study eva luated the pharmacokinetics of canagliflozin 200 mg in subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects.
Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60 and 15 to less than 30 mL/min/1.73 m2 , respectively), but was similar for ESRD (N=8) subjects and healthy subjects.
Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4) and Warnings and Precautions (5.2)].
Canagliflozin was negligibly removed by hemodialysis.
Hepatic Impairment
Relative to subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC∞ of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B (moderate hepatic impairment) following administration of a single 300 mg dose of canagliflozin.
These differences are not considered to be clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment [see Use in Specific Populations (8.7)].
advertisementPharmacokinetics Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race
Based on the population PK analysis with data collected from 1526 subjects, age, body mass index (BMI)/weight, gender, and race do not have a clinically meaningful effect on pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)].
Pediatric
Studies characterizing the pharmacokinetics of canagliflozin in pediatric patients have not been conducted.
Drug Interaction Studies
In Vitro Assessment of Drug Interactions
Canagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is a weak inhibitor of P-gp.
Canagliflozin is also a substrate of drug transporters P-glycoprotein (P-gp) and MRP2.
In Vivo Assessment of Drug Interactions
Table 5: Effect of Co−Administered Drugs on Systemic Exposures of Canagliflozin Co-Administered Drug Dose of Co-Administered Drug * Dose of Canagli
