Preclinical Modeling and Simulation to Explore the Tissue/Plasma Exposure and Pharmacodynamic Effect of Vildagliptin in Diabetes Treatment

Figures

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  FIGURE 1. Vildagliptin concentrations versus time profiles in total plasma (n = 7 and 5), free muscle (n = 6 and 6), and free liver (n = 7 and 6) of healthy rats and rats with diabetes, respectively. Mean ±SD.

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  FIGURE 2. Structural PK/PD model developed for VDG free plasma, muscle and liver concentrations and their DPP‐4 inhibition. Figure shows the schematic representation of the 4‐compartment model describing plasma and microdialysate samples, and the relationship of these free concentrations and the DPP‐4 inhibition. A 1, A 2, A 3, and A 4 are the amounts of drug in central, peripheral, muscle and liver compartments, respectively; V 1, V 2, V 3, and V 4 are the volumes of distribution in central, peripheral, muscle, and liver compartments, respectively; CL is the central clearance, and Q 1 the intercompartmental clearance between central and peripheral compartments; Q in and Q out for muscle and liver are the intercompartmental clearances of entrance and exit in each tissue compartment, respectively; C u is the simulated VDG free tissue or plasma concentration in humans; I max is the maximum inhibition of DPP‐4, and IC50 is the VDG concentration that achieves 50% of DPP‐4 inhibition.

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  FIGURE 3. Goodness of fit plots for the final model. Blue, red, and green dots represent free plasma, muscle and liver data, respectively.

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  FIGURE 4. Visual predictive checks (VPCs) for the final model stratified by plasma, muscle, and liver in healthy and diabetic rats. VPCs are based on 1000 simulations, where dots are the observations and dashed lines and shadow areas are the 10th, 50th, and 90th percentiles.

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  FIGURE 5. Simulated vildagliptin concentrations and DPP‐IV inhibition. Vildagliptin concentration‐time profiles at steady state after 25, 50, and 100 mg after once‐daily (right panel, top) and twice daily (right panel, bottom). DPP‐4 inhibition in time after 25, 50, and 100 mg once daily (left panel, top) and twice daily (left panel, bottom). Dotted line represents the IC50 = 1.35 ng/mL (left panels), and 80% inhibition (right panels).