title: Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus.
abstract: This study characterized single- and multiple-dose pharmacokinetics of canagliflozin and its O-glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RTG ], urinary glucose excretion [UGE0-24h ], and 24-hour mean plasma glucose [MPG0-24h ]) of canagliflozin in subjects with type 2 diabetes. Thirty-six randomized subjects received canagliflozin 50, 100, or 300 mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration-time curve and maximum observed plasma concentration (Cmax ) for canagliflozin and its metabolites increased dose-dependently. Half-life and time at which Cmax was observed were dose-independent. Systemic molar M5 exposure was half that of canagliflozin; M7 exposure was similar to canagliflozin. Steady-state plasma canagliflozin concentrations were reached by Day 4 in all active treatment groups. Pharmacodynamic effects were dose- and exposure-dependent. All canagliflozin doses decreased RTG , increased UGE0-24h , and reduced MPG0-24h versus placebo on Days 1 and 7. On Day 7, placebo-subtracted least-squares mean decreases in MPG0-24h ranged from 42-57 mg/dL with canagliflozin treatment. Adverse events (AEs) were balanced between treatments; no treatment-related serious AEs, AE-related discontinuations, or clinically meaningful adverse changes in routine safety evaluations occurred. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in subjects with type 2 diabetes supports a once-daily dosing regimen.
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ 08869, USA. ddevinen@its.jnj.com
authors.forename: Damayanthi
authors.initials: D
authors.lastname: Devineni
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Curtin
authors.forename: David
authors.initials: D
authors.lastname: Polidori
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Gutierrez
authors.forename: Joseph
authors.initials: J
authors.lastname: Murphy
authors.forename: Sarah
authors.initials: S
authors.lastname: Rusch
authors.forename: Paul L
authors.initials: PL
authors.lastname: Rothenberg
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D020719:Glucuronides / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D005960:Glucosides; D020719:Glucuronides; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin; D005947:Glucose