Population Pharmacokinetic−Pharmacodynamic Modeling of Carvedilol to Evaluate the Effect of Cytochrome P450 2D6 Genotype on the Heart Rate Reduction

Figures

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  Fig. 1. Final PK−PD model structure of carvedilol. The PD model was developed based on HR changes detected from isoproterenol sensitivity tests linked to the PD model. The final PK−PD model describes carvedilol PK and HR response to carvedilol. C = carvedilol concentration, D = isoproterenol dosage, ED50 = half-maximal effective isoproterenol dosage, Emax = maximal effect of isoproterenol, HR = heart rate, IC50 = half-maximal inhibitory carvedilol concentration, k = elimination rate constant of isoproterenol, k10 = elimination rate constant of carvedilol from the central compartment, k12 = rate transfer constant from the central compartment to the peripheral compartment, k21 = rate transfer constant from the peripheral compartment to the central compartment, PD = pharmacodynamic, PK = pharmacokinetic, Tlag = lag time for zero-order absorption.

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  Fig. 2. Goodness-of-fit plots of carvedilol and visual predictive checks for the final PK model of carvedilol. (A) Goodness-of-fit plots of the final PK model. Open circles indicate observations; solid black lines are identity lines; red lines represent locally weighted scatterplot smoothing. Visual predictive checks of the final PK model (B) after a single 12.5-mg dose of carvedilol and (C) after multiple 25-mg doses of carvedilol. Open circles represent carvedilol plasma concentrations; solid lines represent the 5th (blue), median (red), and 95th (blue) concentration percentiles; blue and red areas indicate the 90% confidence interval of the simulated concentrations of each percentile. PK = pharmacokinetic.

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  Fig. 3. Goodness-of-fit plots of heart rate and visual predictive checks for the final PK−PD model. (A) Goodness-of-fit plots of the final PK−PD model. Open circles indicate observations; solid black lines are identity lines; red lines represent locally weighted scatterplot smoothing. Visual predictive checks for HR after IST (B) in baseline, (C) after a single 12.5-mg dose of carvedilol and (D) after multiple 25-mg doses of carvedilol. Open circles represent carvedilol plasma concentrations; solid lines represent the 5th (blue), median (red), and 95th (blue) concentration percentiles; blue and red areas indicate the 90% confidence interval of the simulated concentrations of each percentile. PK = pharmacokinetic, PD = pharmacodynamic, IST = isoproterenol sensitivity test.