Population pharmacokinetic and pharmacodynamic model of evogliptin: Severe uremia increases the bioavailability of evogliptin

FIGURE 1. Schematic representation of the population PK/PD model of evogliptin. A population PK model is based on a two‐compartment model with first‐order oral absorption. The PD model is described by a direct link E max model. F1, relative bioavailability; Ka, first‐order absorption rate constant; CL/F, apparent clearance; Vc/F, apparent volume of distribution of the central compartment; Vp/F, apparent volume of distribution of the peripheral compartment; and Q/F, apparent intercompartmental clearance.

FIGURE 2. Visual diagnostics for the final PK model. (a) Observed versus individual predicted evogliptin concentrations. (b) Observed versus population‐predicted evogliptin concentrations. (c) Conditional weighted residuals over population predicted concentrations. (d) Conditional weighted residuals over time. Red lines represent the regression fit, whereas solid gray lines represent the lines of identity. (e) Prediction‐corrected VPC plots. The red line indicates the median and the blue lines indicate the 5% and 95% percentile. Shaded parts are 90% confidence intervals of predicted values. Dots represent individual observations.

FIGURE 3. Observed data overlaid with simulated data of the PD model. The red line indicates the median and the blue box indicates the 5% and 95% prediction intervals. Dots represent individual observations. A direct‐link sigmoidal E max model was used to describe the PD effect. DPP‐4, dipeptidyl peptidase‐4; PD, pharmacodynamics.

FIGURE 4. Box diagram of C max and AUC0–120 simulated in different scenarios. The bold horizontal line is the median level. Scenario A was used as a reference. Details of the dosing scenarios are presented in Table 2. AUC0–120, area under the concentration–time curve from time 0 to 120 h; C max, maximum concentration.