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. 2022 Aug 17:15:4575-4583.
doi: 10.2147/IDR.S373348. eCollection 2022.

Population-Based Pharmacokinetics and Dose Optimization of Imipenem in Vietnamese Critically-Ill Patients

Thanh D Dinh  1   2 , Hung N Nguyen  1 , Ba Hai Le  1 , Thuy T T Nguyen  1 , Huong T L Nguyen  1
Affiliations

Population-Based Pharmacokinetics and Dose Optimization of Imipenem in Vietnamese Critically-Ill Patients

Thanh D Dinh et al. Infect Drug Resist. .

Abstract

Purpose: The purpose of this study was to characterize the population-based pharmacokinetic (POP-PK) profile of imipenem in Vietnamese adult patients and to assess the probability of target attainment (PTA) of the pharmacokinetic/pharmacodynamic (PK/PD) parameter to determine the optimal dose.

Patients and methods: A POP-PK model of imipenem was developed in patients with severe infection from a 1500-bed general hospital in Vietnam, using MONOLIX 2019. After the initial dose infusion, 6 blood samples per patient were collected to measure plasma imipenem levels. Eight covariates (eg, age, weight) were investigated to ascertain their influence on imipenem's PK. Monte Carlo simulations were performed to determine the PTA for the time in which the total steady-state imipenem concentrations remained above the MIC (T>MIC) for 40% and 100% of the dosing interval.

Results: The best fit to the PK data was a two-compartment model with inter-individual variability (IIV) in clearance (CL), central volume of distribution (Vc), intercompartmental clearance (Q), and peripheral volume of distribution (Vp). Only creatinine clearance was retained as a covariate on CL in the final model. The typical value of CL and Vc were estimated to be 4.79 L/h and 11.1 L, respectively. The between-subject variability in this population was noted to be high (>38%, especially for IIV on Q at 110%). Prolonged or continuous infusion demonstrated efficacy (40% T>MIC) against bacteria with a MIC of 4mg/L. To achieve 100% T>MIC or bacteria with MIC>4 mg/L, however, the number of doses must be increased while maintaining the same daily dose for the 3-hour prolonged infusion regimen.

Conclusion: A population pharmacokinetic model of imipenem was developed for Vietnamese adult patients with severe illness. By using Monte Carlo simulation, the appropriate dose has been suggested based on the bacterial MIC value and the targeted PK/PD goal.

Keywords: Monte Carlo; PK/PD; carbapenem; imipenem; pharmacokinetic modeling.

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Conflict of interest statement

The authors report no conflicts of interest in this work; the authors have no relevant financial or non-financial interests to disclose.

Figures

Figure 1
Figure 1
GOF plots of final models showing observed versus population predicted concentration (A), observed vs individual predicted concentration (B).
Figure 2
Figure 2
Scatter plot of the residuals: Individual weighted residuals (IWRES), seen on the left-hand side of the figure, versus time after dose (top) and concentration (bottom); Normalized Prediction Distribution Error (NDPE, 1000 replicates), seen on the right-hand side of the figure, versus time after dose (top) and concentration (bottom).
Figure 3
Figure 3
Visual Predictive Checks of observed imipenem concentrations (solid line) along with 10th, 50th and 90th percentiles overlaid on median (dashed line) and 90% prediction intervals (shaded region) of simulated concentrations generated from final model (1000 replicates).
Figure 4
Figure 4
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: <30, 30–60, 60–90, and >90 mL/min.
See this image and copyright information in PMC

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