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.)

Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children?

“…But if we looked at each amoxicillin studies in detail, we observed a large variability on amoxicillin clearance values as for piperacillin, explained by the same maturation process described previously (61) since numerous studies have been conducted in preterms and neonates (22,24,47,50). For imipenem, our review showed increased median clearance (0.36 L/h/kg vs 0.16 L/h/kg in adults) and volume of distribution (0.57 L/kg vs 0.16 L/kg in adults) in the pediatric population (32,53). However, the values only represent neonates and young children, a different maturation system could explain this increase compared to adults.…”

Model-Informed Precision Dosing of Imipenem in an Obese Adolescent Patient with Augmented Renal Clearance and History of Schizophrenia

“…In this model, the age range of pediatric patients was 2-12 years old, and the average weight was only 19 kg, but the average CL CR of these pediatric patients reached 223 mL/min. 22 In Bai's two-compartment model including ARC adults, the average weight of the included patients was 89 kg, and the average CL CR was 193 mL/min, which was close to this case except for the age range. 23 Although the age ranges of these two models do not cover this case and the patient populations are different, the two models both included patients with high CL CR levels, and the prediction efficacies were satisfactory.…”

“…Thus, we searched reported PPK models for imipenem in patients with similar characteristics and compared the suitability of the model by mean absolute prediction error (MAPE) using the existing TDM results. [21][22][23][24][25] The calculation method for MAPE is as follows: first, we calculated the difference rPE (relative prediction errors) between the observed values and predicted values of TDM (rPEi = 2*(Cpred-Cobs, i)/(Cpred+Cobs, i), i: individual simulation value). Then, we calculated the absolute values of these rPE (|rPEi|), and finally average the absolute values of these differences to obtain MAPE.…”

“…26,27 NONMEM (ICON Development Solution, version 7.5.0) software was used in the study. Figure1shows the MPAEs of three models, which were developed in children (Dong's Model22 ), adult patients with ARC (Fratoni's Model21 ), and general adult patients (Bai's Model23 ). In Dong's Model, the PK parameters consisted of V 1 , V 2 , Q and CL (V1, central volume of distribution; V2, peripheral volume of distribution; Q, intercompartmental clearance; CL, clearance).…”

Advancing pediatric antimicrobial stewardship: Has pharmacodynamic dosing for gram-negative infections taken effect?

“…[4][5][6][7][8][9][10] Utilizing prolonged or continuous infusion allows adequate time above the minimum inhibitory concentration (MIC) for the unbound antibiotic (fT>MIC) needed for bactericidal activity, as demonstrated in both adult and pediatric studies. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In these analyses, the standard dosing of β-lactams and fluoroquinolones used to treat gram-negative infections is often reported to be inadequate due to the increasing MIC of gram-negative bacteria. [19][20][21] Although a few cases using these approaches in children have been reported, the extent of adoption of these dosing strategies throughout pediatric practice is unknown.…”