A systems pharmacology model of SGLT2 and SGLT1 inhibition to understand mechanism and quantification of urinary glucose excretion after treatment with Dapagliflozin, Canagliflozin and Empagliflozin
Tatiana Yakovleva, Victor Sokolov, Kirill Zhudenkov
M&S decisions, Moscow, Russia
Objectives: Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are a class of drugs effective for type 2 diabetes treatment [1]. However, given the overwhelming contribution (>80%) of SGLT2 to renal glucose reabsorption (rGR), it has been expected that SGLT2 inhibitors, at sufficient exposures, would reduce rGR by over 80%. This expectation appeared to be contradicted by the clinical observations that only 30–50% of inhibition in glucose reabsorption was achieved with Dapagliflozin and Canagliflozin [2]. The aim of the work was to evaluate the relative contribution of SGLT2 and SGLT1 to rGR and explain the mechanism underlying this discrepancy in clinical data, using a quantitative systems pharmacology (QSP) modeling approach.
Methods: The approach for description of gliflozin distribution and lumen concentration was taken from previously published model [1]. Recent model additionally includes kidney glucose filtration, reabsorption by SGLT2/SGLT1, and urine excretion. Available data from gliflozin clinical studies [3-5] were used to estimate parameters. The drug action mechanism implied the competitive inhibition of glucose reabsorption [2], with corresponding IC50 values [6-8]. The modeling was performed in the IQM software tool (by IntiQuan, derived from the SBTOOLBOX2 software - http://www.intiquan.com/).
Results: The QSP model adequately describes the experimental data on 24-hour UGE after treatment with Dapagliflozin, Canagliflozin and Empagliflozin for healthy subjects. The maximum contribution of SGLT2 to rGR was evaluated to 87%, correlating with in vitro data (80-90%) [9]. The contribution of SGLT2 to rGR without drug administration for healthy subjects in vivo was predicted as 77%. Under the treatment with gliflozins the contribution each of the transporters changes depending on inhibitor dose and has a 35% value for the labelled dose treatment for all considered drugs. The observed UGE level is dependent on IC50 for SGLT1/2 and lumen concentration for each of the drugs.
Conclusions: A QSP model of SGLT1/2 inhibition described the relationship between processes of renal glucose reabsorption and UGE, allowed to estimate the relative contributions of SGLT2 and SGLT1 to total rGR rate, and adequately described the experimental data after treatment with Dapagliflozin, Canagliflozin and Empagliflozin. The model was used to delineate the mechanism underlying the apparent discrepancy in UGE levels, as observed for gliflozin-type compounds.
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