2016 - Lisboa - Portugal

PAGE 2016: Drug/Disease modeling - Other topics
Tatiana Yakovleva

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.

[1] Demin O Jr, Yakovleva T, Kolobkov D, Demin O. Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model. Front Pharmacol. 2014 Oct 13;5:218.
[2] Lu Y, Griffen SC, Boulton DW, Leil TA. Use of systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans. Front Pharmacol. 2014 Dec 10;5:274.
[3] Yang L, Li H, Li H, Bui A, Chang M, Boulton DW. Pharmacokinetic and pharmacodynamic properties of single- and multiple-dose of dapagliflozin, a selective inhibitor of SGLT2, in healthy Chinese subjects. Clin Ther. 2013 Aug;35(8):1211-1222.
[4] Devineni D, Curtin CR, Polidori D, Rothenberg PL. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol. 2013 Jun;53(6):601-10.
[5] Heise T, Seman L, Macha S, Dugi K. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther. 2013 Dec;4(2):331-45.
[6] Grempler R, Thomas L, Eckhardt M. Himmelsbach F. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012 Jan;14(1):83-90.  
[7] Hummel CS, Lu C, Loo DD, Hirayama BA. Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am J Physiol Cell Physiol. 2011 Jan;300(1):C14-21.
[8] Australian Public Assessment Report for Canagliflozin (Invokana, Prominad). 2014 March Therapeutic Goods Administration.
[9] DeFronzo R.A., Davidson J.A., Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. DiabetesObes. Metab. 14, 5–14. 

Reference: PAGE 25 (2016) Abstr 5820 [www.page-meeting.org/?abstract=5820]
Poster: Drug/Disease modeling - Other topics
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