J Korean Med Sci.  2023 Jun;38(22):e173. 10.3346/jkms.2023.38.e173.

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

• Hwang S
• Lee S
• Yoon J
• Chung JY

• KMID: 2542805
• DOI: http://doi.org/10.3346/jkms.2023.38.e173

Abstract

Background
Carvedilol is a beta-adrenergic receptor antagonist primarily metabolized by cytochromes P450 (CYP) 2D6. This study established a carvedilol population pharmacokinetic (PK)–pharmacodynamic (PD) model to describe the effects of CYP2D6 genetic polymorphisms on the inter-individual variability of PK and PD.
Methods
The PK–PD model was developed from a clinical study conducted on 21 healthy subjects divided into three CYP2D6 phenotype groups, with six subjects in the extensive metabolizer (EM, *1/*1, *1/*2), seven in the intermediate metabolizer-1 (IM-1, *1/*10, *2/*10), and eight in the intermediate metabolizer-2 (IM-2, *10/*10) groups. The PK–PD model was sequentially developed, and the isoproterenol-induced heart rate changes were used to establish the PD model. A direct effect response and inhibitory E _max model were used to develop a carvedilol PK–PD model.
Results
The carvedilol PK was well described by a two-compartment model with zeroorder absorption, lag time, and first-order elimination. The carvedilol clearance in the CYP2D6*10/*10 group decreased by 32.8% compared with the other groups. The inhibitory concentration of carvedilol estimated from the final PK–PD model was 16.5 ng/mL regardless of the CYP2D6 phenotype.
Conclusion
The PK–PD model revealed that the CYP2D6 genetic polymorphisms were contributed to the inter-individual variability of carvedilol PK, but not PD.

Keyword

Carvedilol; Cytochrome P-450 Enzyme System; Genetic Variation; Pharmacokinetics; Pharmacodynamics

Figure

• 

  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.

• 

  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.

• 

  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.

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