Population pharmacokinetics and dosing optimization of imipenem in Chinese elderly patients

Abstract

Objectives: To assess the pharmacokinetics and pharmacodynamics of imipenem in a retrospective cohort of hospitalized Chinese older patients.

Methods: A population pharmacokinetic (PPK) model was constructed utilizing a nonlinear mixed-effects modeling approach. The final model underwent evaluation through bootstrap resampling and visual predictive checks. Additionally, a population pharmacokinetic and pharmacodynamic analysis was conducted employing Monte Carlo simulations to investigate the impact of commonly used dosing regimens (0.25 g every 6 h, 0.5 g every 6 h, 0.5 g every 8 h, 1 g every 6 h, 1 g every 8 h, and 1 g every 12 h) on the likelihood of achieving the target therapeutic outcomes.

Results: A total of 370 observations available from 142 patients were incorporated in the PPK model. A two-compartment PPK model with linear elimination best predicted the imipenem plasma concentrations, with the creatinine clearance as a significant covariate of clearance. Typical estimates for clearance, inter-compartmental clearance, central and peripheral volume were 13.1 L·h^-1, 11.9 L·h^-1, 11.7 L, 29.3 L, respectively.

Conclusion: The pharmacokinetics of imipenem in elderly patients were effectively characterized by the established PPK model, which includes creatinine clearance as a key covariate. This research will enhance our understanding of imipenem elimination and support precision dosing in this patient demographic.

Keywords: Monte Carlo; dosing optimization; elderly patients; imipenem; population pharmacokinetics.

FIGURE 1

Diagnostic goodness-of-fit plots for the final model. (A) Scatter plot of imipenem plasma concentration and individual predicted values. (B) Scatter plot of imipenem plasma concentration and population predicted values. (C) Scatter plot of conditional weighted residuals and population predicted values. (D) Scatter plot of conditional weighted residuals and time from last dose. The black dashed line is the reference line, and the red dashed line is the LOWESS trend line.

FIGURE 2

Visual predictive check (VPC) of the final model. The black solid points represent the dependent variable; upper, middle, and lower solid line represent the 95th, 50th and 5th percentiles of the observed concentrations, respectively; The upper, middle, and lower shaded sections represent the 95% confidence interval for the 95th, 50th, and 5th percentiles of the simulated concentrations, respectively.

FIGURE 3

Probability of target attainment (PTA) of various imipenem dose regimens with a target of 40% (upper panels) and 100%T > MIC (lower panels), stratified based on patient renal function:0 <-0, 30–60, 60–90, and 90–120 mL/min.