Pharmacokinetics and Pharmacodynamics of Canagliflozin, a Sodium Glucose Co‐Transporter 2 Inhibitor, in Subjects With Type 2 Diabetes Mellitus. (14th May 2013)

• Record Type: Journal Article
• Authors: Devineni, Damayanthi; Curtin, Christopher R.; Polidori, David; Gutierrez, Maria J.; Murphy, Joseph; Rusch, Sarah; Rothenberg, Paul L.
• Is Part Of: Journal of clinical pharmacology. Volume 53:Number 6(2013:Jun.)
• Page Start: 601
• Page End: 610
• Publication Date: 2013-05-14
• Subjects: Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.88
• Languages: English
• ISSNs: 0091-2700

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jcph88-sec-0001" sec-type="section"> <p>This study characterized single‐ and multiple‐dose pharmacokinetics of canagliflozin and its <italic>O</italic>‐glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RT<sub>G</sub>], urinary glucose excretion [UGE<sub>0–24h</sub>], and 24‐hour mean plasma glucose [MPG<sub>0–24h</sub>]) 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 (C<sub>max</sub>) for canagliflozin and its metabolites increased dose‐dependently. Half‐life and time at which C<sub>max</sub> 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 RT<sub>G</sub>, increased UGE<sub>0–24h</sub>, and reduced MPG<sub>0–24h</sub> versus placebo on Days 1 and 7. On Day 7, placebo‐subtracted least‐squares mean decreases in MPG<sub>0–24h</sub> 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.</p> </sec> </abstract>