Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology

Maurer, Tristan S.; Ghosh, Avijit; Haddish‐Berhane, Nahor; Sawant-Basak, Aarti; Boustany-Kari, Carine M.; She, Li; Leininger, Michael T.; Zhu, Tong; Tugnait, Meera; Yang, Xin; Kimoto, Emi; Mascitti, Vincent; Robinson, Ralph P.

doi:10.1208/s12248-011-9297-2

Cited by 32 publications

(45 citation statements)

References 35 publications

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“…Several mathematical models for SGLT‐mediated renal glucose reabsorption have been reported, including: rat models; mice models; a PK/PD model of dapagliflozin in rats; a semi‐mechanistic model of SGLT2 inhibitor efficacy; a physiologically based PK/PD model of canagliflozin; and a systems pharmacology model of dapagliflozin and canagliflozin . We reviewed the strengths and shortcomings of these models of renal glucose filtration and SGLT pharmacology to arrive at the structure and parameterization used in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its large contribution (~80%) to renal glucose reabsorption in healthy individuals, complete inhibition of SGLT2 only results in a 30% to 50% renal glucose reabsorption decrease in people with T2DM. Simple hypotheses explaining this phenomenon have been proposed, for example, insufficient drug concentration in the tubular lumen to completely inhibit SGLT2, or enhancement of SGLT1‐dependent glucose reabsorption . The underlying drivers may, however, be more complex.…”

Section: Introductionmentioning

confidence: 99%

“…Simple hypotheses explaining this phenomenon have been proposed, for example, insufficient drug concentration in the tubular lumen to completely inhibit SGLT2, 5 or enhancement of SGLT1-dependent glucose reabsorption. 6 The underlying drivers may, however, be more complex.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors

Yakovleva¹,

Соколов²,

Chu

et al. 2019

Diabetes Obesity Metabolism

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Aim To develop a quantitative drug‐disease systems model to investigate the paradox that sodium‐glucose co‐transporter (SGLT)2 is responsible for >80% of proximal tubule glucose reabsorption, yet SGLT2 inhibitor treatment results in only 30% to 50% less reabsorption in patients with type 2 diabetes mellitus (T2DM). Materials and methods A physiologically based four‐compartment model of renal glucose filtration, reabsorption and excretion via SGLT1 and SGLT2 was developed as a system of ordinary differential equations using R/IQRtools. SGLT2 inhibitor pharmacokinetics and pharmacodynamics were estimated from published concentration‐time profiles in plasma and urine and from urinary glucose excretion (UGE) in healthy people and people with T2DM. Results The final model showed that higher renal glucose reabsorption in people with T2DM versus healthy people was associated with 54% and 28% greater transporter capacity for SGLT1 and SGLT2, respectively. Additionally, the analysis showed that UGE is highly dependent on mean plasma glucose and estimated glomerular filtration rate (eGFR) and that their consideration is critical for interpreting clinical UGE findings. Conclusions Quantitative drug‐disease system modelling revealed mechanistic differences in renal glucose reabsorption and UGE between healthy people and those with T2DM, and clearly showed that SGLT2 inhibition significantly increased glucose available to SGLT1 downstream in the tubule. Importantly, we found that the findings of lower than expected UGE with SGLT2 inhibition are explained by the shift to SGLT1, which recovered additional glucose (~30% of total).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors

Yakovleva¹,

Соколов²,

Chu

et al. 2019

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

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“…A PK-PD model considering only the function of SGLT2 for renal glucose reabsorption was reported to adequately capture the UGE caused by an SGLT2 inhibitor (Maurer et al, 2011), and the model can simply describe the effect of an SGLT2 inhibitor. However, the lack of SGLT1 function is likely to limit its usefulness.…”

Section: Discussionmentioning

confidence: 99%

In Vitro–In Vivo Correlation of the Inhibition Potency of Sodium-Glucose Cotransporter Inhibitors in Rat: A Pharmacokinetic and Pharmacodynamic Modeling Approach

Yamaguchi

Kato

Suzuki

et al. 2013

J Pharmacol Exp Ther

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To evaluate the relationship between the in vitro and in vivo potency of sodium-glucose cotransporter (SGLT) inhibitors, a pharmacokinetic and pharmacodynamic (PK-PD) study was performed using normal rats. A highly selective SGLT2 inhibitor, tofogliflozin, and four other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2, versus SGLT1 were used as test compounds, and the time courses for urinary glucose excretion (UGE) and the plasma glucose and compound concentrations were monitored after administration of the compounds. A PK-PD analysis of the UGE caused by SGLT inhibition was performed on the basis of a nonlinear parallel tube model that took into consideration the consecutive reabsorption by different glucose transport properties of SGLT2 and SGLT1. The model adequately captured the time course of cumulative UGE caused by SGLT inhibition; then, the in vivo inhibition constants (K i ) of inhibitors for both SGLT1 and SGLT2 were estimated. The in vivo selectivity toward SGLT2 showed a good correlation with the in vitro data (r 5 0.985; P , 0.05), with in vivo K i values for SGLT2 in the range of 0.3-3.4-fold the in vitro data. This suggests that in vitro inhibition potency to both SGLT2 and SGLT1 is reflected in vivo. Furthermore, the complementary role of SGLT1 to SGLT2 and how selectivity toward SGLT2 affects the inhibitory potency for renal glucose reabsorption were discussed using the PK-PD model.

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“…Although previous studies have reported particular PK-PD models to evaluate the UGE of SGLT2 inhibitors, [13][14][15][16][17][18][19] only four have adopted the mechanism-based PK-PD models: the PK-PD model for tofogliflozin in rats 16,17) and the PK-PD model of dapagliflozin and canagliflozin in humans. 18,19) In these studies, the investigators adopted the physiological construction of the proximal tubule in the kidney and the kinetics of competitive SGLT1/2 inhibition in their PK-PD model and successfully described the time course of UGE.…”

Section: )mentioning

confidence: 99%

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus

Samukawa

Mutoh

Chen

et al. 2017

Biological & Pharmaceutical Bulletin

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Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that reduces hyperglycemia in type 2 diabetes mellitus (T2DM) by promoting urinary glucose excretion (UGE). A clinical pharmacology study conducted in Japanese patients with T2DM confirmed dose-dependency of UGE with once-daily administration of luseogliflozin; however, the reason for sustained UGE after plasma luseogliflozin decreased was unclear. To elucidate the effect of inhibition rate constants, K on and K off , and to explain the sustained UGE, a pharmacokinetic-pharmacodynamic (PK-PD) model was built based on the mechanisms of glucose filtration in the glomerulus and reabsorption in the renal proximal tubule of kidney as well as the kinetics of competitive inhibition of SGLT1/2 and inhibition rate constants of SGLT2, by using UGE and plasma glucose levels and luseogliflozin concentrations. This acquired population PK-PD model adequately described the sustained UGE and the estimated population means of the inhibition constant for SGLT2 (K i2 ) and inhibition-rate constants for SGLT2 (K on and K off ) were 0.31-and 3.6-fold lower or higher than the in vitro values. Because the dissociation half-time of luseogliflozin from SGLT2 calculated from K off , 6.81 h, was consistent with the value in vitro, we considered that the sustained UGE could be explained by the long dissociation half-time. Moreover, by calculating the SGLT2 inhibition ratio using the model, we discuss other properties of the UGE time course after luseogliflozin administration.Key words luseogliflozin; urinary glucose excretion; pharmacokinetic-pharmacodynamic model; sodium glucose co-transporter 2; type 2 diabetes mellitus In the human kidney, plasma glucose entering the glomeruli is filtered into the nephron fluid, and the filtered glucose is reabsorbed almost completely by two isoforms of sodium glucose co-transporter (SGLT), SGLT2 and SGLT1. SGLT2 is a high-capacity, low-affinity glucose transporter located in the early convoluted segment (S1 segment) of the proximal tubule that mediates 90% of renal glucose reabsorption. SGLT1 is a high-affinity, low-capacity glucose transporter located in the straight section of the proximal tubule (S3 segment) that is responsible for 10% of renal glucose reabsorption. 1) Inhibition of SGLT2 causes glucose excretion in urine and a reduction in plasma glucose. Several SGLT2 inhibitors have been developed for treatment of type 2 diabetes mellitus (T2DM). 2-4)Luseogliflozin is a novel selective SGLT2 inhibitor 5,6) currently marketed for the treatment of T2DM. The recommended dose is 2.5 mg (or 5 mg depending on the symptoms) once daily before or after breakfast. Studies in Japanese patients with T2DM have confirmed that treatment with luseogliflozin increases urinary glucose excretion (UGE) and reduces plasma glucose levels. [7][8][9][10][11][12] In a clinical pharmacology study conducted in Japanese patients with T2DM, reported by Sasaki et al., intensive sampling of UGE (nine sampling intervals a day) was performed and UGE ...

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Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology

Cited by 32 publications

References 35 publications

Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors

Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors

In Vitro–In Vivo Correlation of the Inhibition Potency of Sodium-Glucose Cotransporter Inhibitors in Rat: A Pharmacokinetic and Pharmacodynamic Modeling Approach

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus

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