Differentiating the Sodium‐Glucose Cotransporter 1 Inhibition Capacity of Canagliflozin vs. Dapagliflozin and Empagliflozin Using Quantitative Systems Pharmacology Modeling. (6th March 2020)

• Record Type: Journal Article
• Authors: Sokolov, Victor; Yakovleva, Tatiana; Chu, Lulu; Tang, Weifeng; Greasley, Peter J.; Johansson, Susanne; Peskov, Kirill; Helmlinger, Gabriel; Boulton, David W.; Penland, Robert C.
• Is Part Of: CPT: pharmacometrics & systems pharmacology. Volume 9:Number 4(2020)
• Page Start: 222
• Page End: 229
• Publication Date: 2020-03-06
• Subjects: Pharmacokinetics -- Periodicals; Pharmacology -- Periodicals; Pharmacokinetics; Periodicals; 615.05
• DOI: 10.1002/psp4.12498
• Languages: English
• ISSNs: 2163-8306

Abstract

Abstract : The aim of this research was to differentiate dapagliflozin, empagliflozin, and canagliflozin based on their capacity to inhibit sodium‐glucose cotransporter (SGLT) 1 and 2 in patients with type 2 diabetes using a previously developed quantitative systems pharmacology model of renal glucose filtration, reabsorption, and excretion. The analysis was based on pooled, mean study‐level data on 24‐hour urinary glucose excretion, average daily plasma glucose, and estimated glomerular filtration rate collected from phase I and II clinical trials of SGLT2 inhibitors. Variations in filtered glucose across clinical studies were shown to drive the apparent differences in the glucosuria dose–response relationships among the gliflozins. A normalized dose–response analysis demonstrated similarity of dapagliflozin and empagliflozin, but not canagliflozin. At approved doses, SGLT1 inhibition by canagliflozin but not dapagliflozin or empagliflozin contributed to ~ 10% of daily urinary glucose excretion.