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Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model.

Demin O, Yakovleva T, Kolobkov D, Demin O - Front Pharmacol (2014)

Bottom Line: To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2.All the compounds exhibited almost 100% inhibition of SGLT2.Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family).

View Article: PubMed Central - PubMed

Affiliation: Laboratory Alpha, Institute for Systems Biology Moscow Moscow, Russia.

ABSTRACT
The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin, and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30-50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies). All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family).

No MeSH data available.


Related in: MedlinePlus

Levels of SGLT2 inhibition after drug administration. Levels of SGLT2 inhibition following simulation of multiple administrations of labeled doses of marketed SGLT2 inhibitors and maximal doses of other SGLT2 inhibitors approved for phase 2/3 studies. Colors of curves correspond to different compounds: black—10 mg QD dapagliflozin; blue—300 mg QD canagliflozin; red—25 mg QD empagliflozin; green—300 mg QD ipragliflozin; pink—40 mg QD tofogliflozin. Model simulations are presented with 95% confidence bands.
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Figure 11: Levels of SGLT2 inhibition after drug administration. Levels of SGLT2 inhibition following simulation of multiple administrations of labeled doses of marketed SGLT2 inhibitors and maximal doses of other SGLT2 inhibitors approved for phase 2/3 studies. Colors of curves correspond to different compounds: black—10 mg QD dapagliflozin; blue—300 mg QD canagliflozin; red—25 mg QD empagliflozin; green—300 mg QD ipragliflozin; pink—40 mg QD tofogliflozin. Model simulations are presented with 95% confidence bands.

Mentions: To compare the efficacies of each compound, the level of SGLT2 inhibition was simulated after administration of equal doses (20 mg) (Supplementary Figure 24), labeled doses of marketed inhibitors, and maximal doses of other inhibitors approved for phase 2/3 studies (Figure 11). For all compounds, administration of equal or labeled/maximal approved doses resulted in almost 100% inhibition of SGLT2. Therefore, the difference in efficacy of the tested SGLT2 inhibitors was not significant.


Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model.

Demin O, Yakovleva T, Kolobkov D, Demin O - Front Pharmacol (2014)

Levels of SGLT2 inhibition after drug administration. Levels of SGLT2 inhibition following simulation of multiple administrations of labeled doses of marketed SGLT2 inhibitors and maximal doses of other SGLT2 inhibitors approved for phase 2/3 studies. Colors of curves correspond to different compounds: black—10 mg QD dapagliflozin; blue—300 mg QD canagliflozin; red—25 mg QD empagliflozin; green—300 mg QD ipragliflozin; pink—40 mg QD tofogliflozin. Model simulations are presented with 95% confidence bands.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4195280&req=5

Figure 11: Levels of SGLT2 inhibition after drug administration. Levels of SGLT2 inhibition following simulation of multiple administrations of labeled doses of marketed SGLT2 inhibitors and maximal doses of other SGLT2 inhibitors approved for phase 2/3 studies. Colors of curves correspond to different compounds: black—10 mg QD dapagliflozin; blue—300 mg QD canagliflozin; red—25 mg QD empagliflozin; green—300 mg QD ipragliflozin; pink—40 mg QD tofogliflozin. Model simulations are presented with 95% confidence bands.
Mentions: To compare the efficacies of each compound, the level of SGLT2 inhibition was simulated after administration of equal doses (20 mg) (Supplementary Figure 24), labeled doses of marketed inhibitors, and maximal doses of other inhibitors approved for phase 2/3 studies (Figure 11). For all compounds, administration of equal or labeled/maximal approved doses resulted in almost 100% inhibition of SGLT2. Therefore, the difference in efficacy of the tested SGLT2 inhibitors was not significant.

Bottom Line: To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2.All the compounds exhibited almost 100% inhibition of SGLT2.Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family).

View Article: PubMed Central - PubMed

Affiliation: Laboratory Alpha, Institute for Systems Biology Moscow Moscow, Russia.

ABSTRACT
The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin, and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30-50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies). All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family).

No MeSH data available.


Related in: MedlinePlus