Population Pharmacokinetics and Dosing Optimization of Imipenem in Children with Hematological Malignancies

Abstract

Imipenem is widely used for the treatment of children with serious infections. Currently, studies on the pharmacokinetics of imipenem in children with hematological malignancies are lacking. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population. After children were treated with imipenem-cilastatin (IMP-CS), blood samples were collected from the children and the concentrations of imipenem were quantified using high-performance liquid chromatography with UV detection. Then, a population-level pharmacokinetic analysis was conducted using NONMEM software. Data were collected from 56 children (age range, 2.03 to 11.82 years) with hematological malignancies to conduct a population pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be the most suitable. The parameters of current weight, age, and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1%, and 67.1% of the children reached the pharmacodynamic target (the percentage of the time during the total dosing interval that the free drug concentration remains above the MIC of 70%) against sensitive pathogens with an MIC of 0.5 mg/liter with imipenem at 15, 20, and 25 mg/kg of body weight every 6 h (q6h), respectively. However, only 11.1% of the children achieved the pharmacodynamic target against Pseudomonas aeruginosa isolates with an MIC of 2 mg/liter at a dose of 25 mg/kg q6h. The population pharmacokinetics of imipenem were assessed in children. The current dosage regimens of imipenem result in underdosing against resistant pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h. (The study discussed in this paper has been registered at ClinicalTrials.gov under identifier NCT03113344.).

Keywords: children; dosing; imipenem; population pharmacokinetics.

Copyright © 2019 American Society for Microbiology.

Figures

FIG 1

Imipenem concentration versus time.

FIG 2

Relationship between imipenem CL and CW (A), age (B), and CLCR (C).

FIG 3

Model evaluation for imipenem. (A) PRED versus DV. (B) IPRED versus DV. (C) CWRES versus time. (D) CWRES versus PRED. (E) QQ plot of the distribution of NPDE versus the theoretical N(0,1) distribution. (F) Histogram of the distribution of NPDE, with the density of the standard Gaussian distribution overlaid. (G) Prediction-corrected visual predictive check. The circles represent the prediction-corrected observed concentrations. The solid line represents the median prediction-corrected observed concentrations. The observed 5% and 95% percentiles are presented with dashed lines.

FIG 4

Probability of target attainment (70% fT>MIC) for imipenem at different dose regimens with MICs of 0.5 mg/liter and 2 mg/liter.

FIG 5

Inclusion and exclusion criteria.