Differentiating the SGLT1 inhibition capacity of canagliflozin vs. dapagliflozin and empagliflozin using quantitative systems pharmacology modeling

AbstractThe 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 (U GE), average daily plasma glucose and estimated glomerular filtration rate collected from phase 2 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 glifloz ins. 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.

Source: CPT: Pharmacometrics and Systems Pharmacology - February 28, 2020 Category: Drugs & Pharmacology Authors: Victor Sokolov, Tatiana Yakovleva, Lulu Chu, Weifeng Tang, Peter J. Greasley, Susanne Johansson, Kirill Peskov, Gabriel Helmlinger, David W. Boulton, Robert C. Penland Tags: ARTICLE Source Type: research