Metoprolol Dose Equivalence in Adult Men and Women Based on Gender Differences: Pharmacokinetic Modeling and Simulations

Abstract

Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration-time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men.

Keywords: gender differences; metoprolol; modeling; monolix; pharmacokinetics.

Figure 1

Goodness-of-fit plots for the R-metoprolol (a) and (b) and S-metoprolol (c) and (d) enantiomers for males (b) and (d) and females (a) and (c). The x-axes depict the predicted plasma levels and the y-axes depict the observed metoprolol plasma levels.

Figure 2

Model parameter validation using pharmacokinetic dosing simulations using the gender-stratified model parameters and the original Luzier et al. experimental plasma concentrations. Female (orange—higher line) and male (blue—lower line) dosing simulations for the nine 100 mg metoprolol doses illustrate an adequate fit to the experimental results.

Figure 3

Dose-finding simulation results of two 100 mg doses of metoprolol every 12 h, for (a) men and (b) women. The results are based on the S-metoprolol modeling parameters where the solid lines illustrate the typical value of plasma concentrations and the shaded bands represent the 10th and 90th percent confidence interval for 3000 virtual patients.

Figure 4

Goodness-of-fit plots for the observed versus predicted model diagnostics of the population (a) fit and the individual (b) fit of metoprolol plasma concentrations in healthy young men and women. The x-axis in (a) is the population predicted plasma concentrations while the x-axis on the right (b) illustrates the individual predicted concentrations based on the Stochastic Approximation Expectation–Maximization (SAEM) algorithm. The y-axes are the observed metoprolol concentrations.

Figure 5

The prediction-corrected visual predictive check (PC-VPC) for a clinical trial simulation of metoprolol concentration–time plasma levels for healthy young women (a) and men (b). The shaded regions depict the 95% confidence intervals around the 10th, 50th, and 90th percentile range of plasma concentrations, while the solid line illustrates the average population pharmacokinetic metoprolol concentration. Emp. Prctile is the empirical percentile, prctile out is the percentile out, P.I. 90%, 50%, 10% and P.I. out are the 95% confidence intervals for the 10^th, 50^th, and 90^th percentiles while the P.I. out is the data predicted percentile out of the PC-VPC prediction interval(s).