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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

Example of validation of the dapagliflozin model using urine data. Amount of dapagliflozin recovered in urine every 24 h following simulation of multiple administrations of 10 mg QD. Curve represents model simulation and dots represent experimental data. Colors of dots correspond to the different data sources: black—Kasichayanula et al. (2011a), blue—Yang et al. (2013). Model simulation is presented with 95% confidence bands.
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Figure 5: Example of validation of the dapagliflozin model using urine data. Amount of dapagliflozin recovered in urine every 24 h following simulation of multiple administrations of 10 mg QD. Curve represents model simulation and dots represent experimental data. Colors of dots correspond to the different data sources: black—Kasichayanula et al. (2011a), blue—Yang et al. (2013). Model simulation is presented with 95% confidence bands.

Mentions: All data available in the literature was used for model verification and validation (Table 3). Models were calibrated against clinical data obtained in trials where a single dose of SGLT2 inhibitor was administered. By applying the verification strategy described in the Supplementary Materials, we found that: (i) the active secretion of dapagliflozin, canagliflozin, and ipragliflozin from plasma to kidney lumen was equal to zero; (ii) the reabsorption of empagliflozin was equal to zero; and (iii) both active secretion and reabsorption of tofogliflozin were equal to zero. The appropriate choice of model parameters was validated against data obtained from single and multiple dose administration. Figures 2, 3 represent examples of dapagliflozin model calibration using plasma PK and urine recovery data respectively, where data was obtained from single dose trials. Figures 4, 5 also represent examples of dapagliflozin model validation against plasma PK and urine recovery data respectively, but data was obtained from multiple dose trials. The 95% confidence bands captured the variability in clinical data (Figures 4, 5); therefore, we concluded that model validation was of satisfactory quality. Several additional figures demonstrating the quality of verification and validation in dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin models are presented in the Supplementary Materials (Supplementary Figures 1–16). These figures demonstrate that the models enable a satisfactory description of plasma PK and recovery of SGLT2 inhibitors in urine.


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

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

Example of validation of the dapagliflozin model using urine data. Amount of dapagliflozin recovered in urine every 24 h following simulation of multiple administrations of 10 mg QD. Curve represents model simulation and dots represent experimental data. Colors of dots correspond to the different data sources: black—Kasichayanula et al. (2011a), blue—Yang et al. (2013). Model simulation is presented with 95% confidence bands.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Example of validation of the dapagliflozin model using urine data. Amount of dapagliflozin recovered in urine every 24 h following simulation of multiple administrations of 10 mg QD. Curve represents model simulation and dots represent experimental data. Colors of dots correspond to the different data sources: black—Kasichayanula et al. (2011a), blue—Yang et al. (2013). Model simulation is presented with 95% confidence bands.
Mentions: All data available in the literature was used for model verification and validation (Table 3). Models were calibrated against clinical data obtained in trials where a single dose of SGLT2 inhibitor was administered. By applying the verification strategy described in the Supplementary Materials, we found that: (i) the active secretion of dapagliflozin, canagliflozin, and ipragliflozin from plasma to kidney lumen was equal to zero; (ii) the reabsorption of empagliflozin was equal to zero; and (iii) both active secretion and reabsorption of tofogliflozin were equal to zero. The appropriate choice of model parameters was validated against data obtained from single and multiple dose administration. Figures 2, 3 represent examples of dapagliflozin model calibration using plasma PK and urine recovery data respectively, where data was obtained from single dose trials. Figures 4, 5 also represent examples of dapagliflozin model validation against plasma PK and urine recovery data respectively, but data was obtained from multiple dose trials. The 95% confidence bands captured the variability in clinical data (Figures 4, 5); therefore, we concluded that model validation was of satisfactory quality. Several additional figures demonstrating the quality of verification and validation in dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin models are presented in the Supplementary Materials (Supplementary Figures 1–16). These figures demonstrate that the models enable a satisfactory description of plasma PK and recovery of SGLT2 inhibitors in urine.

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