Article Figures & Data
Figures
- Fig. 1.
Chemical structures of luseogliflozin (A), phlorizin (B), and miglitol (C).
- Fig. 2.
Plasma concentration-time profiles for luseogliflozin and phlorizin in rats. (A-1 and B-1) Two-compartment model-fitted profiles in rats after the single intravenous administration of luseogliflozin (0.1 mg/kg) (A-1) and phlorizin (4 mg/kg) (B-1). The closed circles represent the mean observed data +S.D. (n = 3). The solid lines were fitted using a nonlinear least-squares regression analysis. The PK parameters (CL, Vc, k12, k21) in rats for simulating luminal concentrations were obtained by this fitting to the observed data. (A-2 and B-2) Simulated concentration-time profiles in rats after the single oral administration of luseogliflozin (0.1 mg/kg) (A-2) and phlorizin (40 mg/kg) (B-2). The closed circles represent the mean observed data + S.D. (n = 6). The solid lines represent the model-simulated profiles, which were obtained using the ACAT model in GastroPlus.
- Fig. 3.
Simulated luminal concentration-time profiles in rat duodenum (red line) and TAIC after the single oral administration of luseogliflozin (0.1 mg/kg) (A) and phlorizin (40 mg/kg) (B). The dashed lines represent a value 10-fold higher than the IC50 value for SGLT1. The TAIC of luseogliflozin in rats (9 minutes) was shorter than the Tmax of miglitol in rats (28 minutes). On the other hand, the TAIC of phlorizin in rats (75 minutes) was longer.
- Fig. 4.
Plasma levels of miglitol in rats following the oral administration of miglitol alone (1.5 mg/kg, red line) or in combination with concomitant agents. (A) Combination with luseogliflozin (0.1 mg/kg, blue line). (B) Combination with phlorizin (40 mg/kg, green line). The closed circles and triangles represent the observed mean data ± S.D. (n = 6). The data for miglitol alone was referenced from Mizuno-Yasuhira et al. (2014).
- Fig. 5.
Plasma concentration-time profiles for luseogliflozin in humans. The closed circles represent the mean observed data +S.D. (n = 12). (A-1) Two-compartment model-fitted profiles in humans after the single intravenous administration of luseogliflozin (5 mg/individual). The solid line was fitted using a nonlinear least-squares regression analysis. The PK parameters (CL/F, Vc/F, k12, k21) in humans for simulating luminal concentrations were obtained by this fitting to the observed data. (A-2) Simulated concentration-time profiles in humans after the single oral administration of luseogliflozin (5 mg/individual). The solid lines represent the model-simulated profiles, which were obtained using the ACAT model in GastroPlus.
- Fig. 6.
Simulated luminal concentration-time profiles in human duodenum (red line), upper jejunum (green line), and TAIC after the single oral administration of luseogliflozin (5 mg/individual). The dashed line represents a value 10-fold higher than the IC50 value for SGLT1. The TAIC of luseogliflozin in humans (14 minutes) was shorter than the Tmax of miglitol in humans (83 minutes).
- Fig. 7.
Plasma levels of miglitol in humans following the oral administration of miglitol alone (50 mg/individual, red line) or in combination with luseogliflozin (5 mg/individual, blue line). The closed circles and triangles represent the observed mean data ± S.D. (n = 12).
- Fig. 8.
Potential influence of Peff value on the Tmax and Cmax values. The Tmax of luseogliflozin and the Tmax and Cmax of phlorizin were simulated using different values for Peff with other parameters fixed at the same values, as shown in Table 1.
Tables
- TABLE 1
Input parameters for GastroPlus that were used to simulate the luminal concentrations
Property Luseogliflozin in Rats Phlorizin in Rats Luseogliflozin in Humans Input Data Reference/Remarks Input Data Reference/Remarks Input Data Reference/Remarks Physicochemical parameters Molecular formula C23H30O6S — C21H24O10 — C23H30O6S — Molecular weight (g/mol) 434.55 — 436.42 — 434.55 — Reference logP (pH) 2.2 (-1) In-house data 0.25 (-1) Estimated by ADMET Predictor 2.2 (-1) In-house data Dosage form IR: solution — IR: suspension — IR: tablet — Initial dose (mg) 0.03 — 12 — 5 — Dose volume (ml) 2 — 2 — 250 — Solubility (mg/ml at pH = 6.57) 0.0771 In-house data 9.27 (mg/ml at pH = 4.49) Estimated by ADMET Predictor 0.0771 In-house data Diff. coeff. (cm2/s × 105) 0.60 Estimated by ADMET Predictor 0.64 Estimated by ADMET Predictor 0.60 Estimated by ADMET Predictor Mean particle radius (μm) 3.03 In-house data 25.0 Default value 1.22 In-house data Peff (cm/s × 104) 6.23 Estimated from Ka 0.558 Estimated from Ka 27.5 Estimated from Ka Gut physiology Physiology Rat-fasted The stomach transit time was changed to 0.1 h. Rat-fasted The stomach transit time was changed to 0.1 h. Human-fasted — ASF model Opt logD model SA/V6.1 — Opt logD model SA/V6.1 — Opt logD model SA/V6.1 — Pharmacokinetic parameters Body weight (kg) 0.30 — 0.30 — 60 — FPE intestinal 45.7 Estimated 98.8 Estimated 0 — FPE liver 73.3 Estimated 65.4 Estimated 0 — Blood/plasma concentration ratio 0.536 In-house data 0.930 Estimated by ADMET Predictor 0.599 In-house data Fup (%) 5.40 In-house data 6.71 Estimated by ADMET Predictor 4.00 In-house data Renal clearance (l/h/kg) 0 — 0 — 0 — Model 2-compartment — 2-compartment — 2-compartment — CL (l/h) 0.495 Fitted from 0.1 mg/kg iv data 0.766 Fitted from 4 mg/kg iv data CL/F (l/h) Fitted from 5 mg/individual po data 2.83 Vc (l/kg) 1.21 0.877 Vc/F (l/kg) 0.358 k12(1/h) 0.384 0.0352 0.433 k21 (1/h) 0.271 0.535 0.583 ASF, absorption scaling factor; Diff. coeff., diffusion coefficient; Fup, plasma unbound fraction; IR, immediate release; po, oral.
- TABLE 2
Dose regimens and formulations used in the pharmacokinetic and interaction studies in rats
Study Compound Route N Dose (mg/kg) Conc. (mg/ml) Vehicle Formulation Pharmacokinetics Luseogliflozin iv 3 0.1 0.1 10% HP-β-CD Solution Phlorizin iv 3 4 4 PEG400/saline (4:6,v/v) Solution Luseogliflozin po 6 0.1 0.015a 0.5% CMC-Na Solution Phlorizin po 6 40 6 0.5% CMC-Na Suspension Interaction Miglitol aloneb po 6 1.5 0.225a 0.5% CMC-Na Solution Combination Miglitol po 6 1.5 0.225a 0.5% CMC-Na Solution Luseogliflozin 0.1 0.015a Combination Miglitol po 6 1.5 0.225a 0.5% CMC-Na Suspension Phlorizin 40 6 Combination Parameter Ratio of Geometric Mean Point Estimate 90% CI (Combination/Miglitol Alone) Lower Upper Miglitol and luseogliflozin Cmax 0.97 0.85 1.09 AUC0-t 1.12 1.04 1.20 Miglitol and phlorizin Cmax 0.41* 0.23* 0.72* AUC0-t 0.63* 0.38* 1.02 ↵* The 90% CIs of the ratio (combination/miglitol alone) was outside the range of 0.8–1.25.
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