Developmental Population Pharmacokinetics and Dosing Optimization of Cefepime in Neonates and Young Infants

Zhao, Yang; Yao, Bu‐Fan; Kou, Chen; Xu, Huilin; Tang, Bo‐Hao; Wu, Yue‐E; Hao, Guo‐Xiang; Zhang, Xiaopeng; Zhao, Wei

doi:10.3389/fphar.2020.00014

Cited by 20 publications

(16 citation statements)

References 15 publications

(21 reference statements)

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“…A 2-compartment model best described our data, in accordance with previously published studies. [12][13][14] When normalizing PK parameters on our median weight of 4.5 kg for comparison, our CL was similar to values found in neonates (320-536 mL/h/4.5 kg), [14][15][16][17] while being lower than previously reported values in infants and children not supported with ECMO (500-900 mL/h/4.5 kg). 14,18 In addition to the young age of our cohort (median of 2.5 months), we believe our observed low CL may be explained by organ dysfunctions associated with critical illness.…”

Section: Discussionsupporting

confidence: 85%

Pharmacokinetics of Cefepime in Children on Extracorporeal Membrane Oxygenation

Thibault

Moorthy

Vedar

et al. 2022

Pediatric Infectious Disease Journal

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Background: Cefepime is a first-line therapy for Gram-negative infections in children on extracorporeal membrane oxygenation. Cefepime pharmacokinetics (PK) in children on extracorporeal membrane oxygenation still needs to be better established. Methods: This was a prospective single-center PK study. A maximum of 12 PK samples per patient were collected in children <18 years old on extracorporeal membrane oxygenation who received clinically indicated cefepime. External validation of a previously published population PK model was performed by applying the model in a new data set. The predictive performance of the model was determined by calculating prediction errors. Because of poor predictive performance, a revised model was developed using NON-MEM and a combined data set that included data from both studies. Doseexposure simulations were performed using the final model. Optimal dosing was judged based on the ability to maintain free cefepime concentrations above the minimal inhibitory concentration (MIC) for 68% and 100% of the dosing interval. Results: Seventeen children contributed 105 PK samples. The mean (95% CI) and median (interquartile range) prediction errors were 33.7% (19.8-47.7) and 17.5% (−22.6 to 74.4). A combined data set was created, which included 33 children contributing 310 PK samples. The final improved 2-compartment model included weight and serum creatinine on clearance and oxygenator day and blood transfusion on volume of the central compartment. At an MIC of 8 mg/L, 50 mg/kg/dose every 8 hours reached target concentrations. Conclusions: Dosing intervals of 8 hours were needed to reach adequate concentrations at an MIC of 8 mg/L. Longer dosing intervals were adequate with higher serum creatinine and lower MICs.

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Section: Discussionsupporting

confidence: 85%

Pharmacokinetics of Cefepime in Children on Extracorporeal Membrane Oxygenation

Thibault

Moorthy

Vedar

et al. 2022

Pediatric Infectious Disease Journal

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“…Luckily, the combination of population pharmacokinetics and Monte Carlo simulation could be used to recommend the optimum initial regimen, which has been successfully used in many drugs. For example, Zhao et al reported developmental population pharmacokinetics and dosing optimization of cefepime in neonates and young infants (Zhao et al, 2020). Therefore, the present study aimed to recommend the initial dosage regimen for sirolimus improving drug blood level for seizure control in pediatric patients with TSC based on the population pharmacokinetics and Monte Carlo simulation.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Initial Dose Optimization of Sirolimus Improving Drug Blood Level for Seizure Control in Pediatric Patients With Tuberous Sclerosis Complex

et al. 2021

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The purposes of this study were to explore the population pharmacokinetics and initial dose optimization of sirolimus improving drug blood level for seizure control in pediatric patients with tuberous sclerosis complex (TSC). Eighty pediatric patients diagnosed with TSC-related epilepsy were included for analysis. Sirolimus concentrations, physiological and biochemical indexes, and drug combination were collected to build a nonlinear mixed effect (NONMEM) model. Initial dose optimization was simulated by the Monte Carlo method. The weight and concomitant medication of oxcarbazepine affected sirolimus clearance. Without oxcarbazepine, for once-daily sirolimus regimen, the doses of 0.07, 0.06, 0.05, 0.04, and 0.03 mg/kg/day were recommended for weights of 5–7.5, 7.5–11.5, 11.5–19, 19–40, and 40–70 kg, respectively; for twice-daily sirolimus regimen, the doses of 0.05, 0.04, and 0.03 were recommended for weights of 5–8, 8–20, and 20–70 kg, respectively. With oxcarbazepine, for once-daily sirolimus regimen, the doses of 0.09, 0.08, 0.07, 0.06, 0.05, and 0.04 mg/kg/day were recommended for weights of 5–7.5, 7.5–10, 10–13.5, 13.5–20, 20–35, and 35–70 kg, respectively; for twice-daily sirolimus regimen, the doses of 0.06, 0.05, 0.04, and 0.03 were recommended for weights of 5–7, 7–14.5, 14.5–38, and 38–70 kg, respectively. The present study was the first to establish a population pharmacokinetic model of sirolimus improving drug blood level for seizure control in pediatric patients with TSC and recommend the initial dosage regimen.

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“…Opportunistic samples collected from blood remaining after routine laboratory tests as part of clinical care is one of the novel proposed methods 37,38 . However, the opportunistic‐sampling approach also poses issues, such as variability in available sample numbers among patients.…”

Section: Discussionmentioning

confidence: 99%

“…All rights reserved Opportunistic samples collected from blood remaining after routine laboratory tests as part of clinical care is one of the novel proposed methods. 37,38 However, the opportunistic-sampling approach also poses issues such as variability in available sample numbers among patients. The optimal-sampling approach used in the present study will help guide which blood sampling times' data should be noted.…”

Section: Accepted Articlementioning

confidence: 99%

Model‐based approach to sampling optimization in studies of antibacterial drugs for infants and young children

Orito

Kakara

Okada

et al. 2021

Clinical Translational Sci

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Clinical trials for pediatric indications and new pediatric drugs face challenges including the limited blood volume due to the patients' small bodies. In Japan, the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic-resistant bacteria. Regulatory guidelines promote the use of model-based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model-based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

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Developmental Population Pharmacokinetics and Dosing Optimization of Cefepime in Neonates and Young Infants

Cited by 20 publications

References 15 publications

Pharmacokinetics of Cefepime in Children on Extracorporeal Membrane Oxygenation

Pharmacokinetics of Cefepime in Children on Extracorporeal Membrane Oxygenation

Population Pharmacokinetics and Initial Dose Optimization of Sirolimus Improving Drug Blood Level for Seizure Control in Pediatric Patients With Tuberous Sclerosis Complex

Model‐based approach to sampling optimization in studies of antibacterial drugs for infants and young children

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