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

ABSTRACT: Objective:Cefepime is used to treat severe infections in neonates. Pharmacokinetic data have only been evaluated among preterm neonates and population pharmacokinetic model lacked external validation. Hence, our aim is to obtain the population pharmacokinetic parameters of cefepime with large sampling and optimize the cefepime dosage regimen for neonatal infection based on developmental pharmacokinetics-pharmacodynamics. Methods:Blood samples from neonates and young infants treated with cefepime were collected using the opportunistic sampling design. The concentration of cefepime was determined using high performance liquid chromatography with ultraviolet detection. The population pharmacokinetic model was established using NONMEM software. Results:One hundred blood samples from eighty-five neonates were analyzed. The population pharmacokinetics of cefepime were described by a one-compartment model with first-order elimination. Covariate analysis indicated that serum creatinine concentration, postmenstrual age and current weight had significant impact on the pharmacokinetic parameters of cefepime. Monte Carlo simulation results showed that the current dosage regimen (30 mg/kg, q12 h) had a high risk of insufficient dose. For 70% of neonates to obtain a higher free drug concentration than the minimum inhibitory concentration during 70% of the dosing interval, 50 mg/kg q12 h was needed with a susceptibility breakpoint of 4 mg/l. For a minimum inhibitory concentration of 8 mg/l, 40 mg/kg q8 h was recommended for all neonates. Conclusion:A population pharmacokinetic model of cefepime in neonates and young infants was established. According to simulation results based on the developmental pharmacokinetics-pharmacodynamics, different dosage regimens should be given depending on pathogens and the postmenstrual age.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC7010644 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Zhao Yang Y Yao Bu-Fan BF Kou Chen C Xu Hai-Yan HY Tang Bo-Hao BH Wu Yue-E YE Hao Guo-Xiang GX Zhang Xin-Ping XP Zhao Wei W

Frontiers in pharmacology 20200204

<h4>Objective</h4>Cefepime is used to treat severe infections in neonates. Pharmacokinetic data have only been evaluated among preterm neonates and population pharmacokinetic model lacked external validation. Hence, our aim is to obtain the population pharmacokinetic parameters of cefepime with large sampling and optimize the cefepime dosage regimen for neonatal infection based on developmental pharmacokinetics-pharmacodynamics.<h4>Methods</h4>Blood samples from neonates and young infants treate ...[more]

PMID: 32116695

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Project description:Objectives: The pharmacokinetics (PK) of teicoplanin differs in children compared with adults. Our aim was to determine the PK of teicoplanin in an Asian pediatric population and to optimize dosage regimens. Methods: This was a retrospective PK study and all the data were collected from hospitalized children. We developed a population PK model using sparse data, and Monte Carlo simulation was used to assess the ability of standard teicoplanin regimen and other different dosage regimens. The optimal dosing regimens were defined as achieving the target trough concentration (C min) of 10 mg/L and pharmacokinetic/pharmacodynamic (PK/PD, [AUC24/MIC]) of 125 for moderate infection. For severe infection, the optimal dosing regimens were defined as achieving the target 15 mg/L and AUC24/MIC of 345. Results: 159 children were included and 1.5 samples/children on average were provided. Estimated clearance of teicoplanin was 0.694 L/h (0.784/L/h/70 kg) and volume of distribution was 1.39 L. Teicoplanin standard loading dose was adequate for moderate infection, while 13 mg/kg was needed for severer infection. With standard maintenance doses, both patients with moderate and severe infection failed to achieve the target C min. 12 and 16 mg/kg/day were required to achieve a C min ≥ 10 and 15 mg/L, respectively. However, standard maintenance dose was adequate to achieve AUC24/MIC ≥ 125 for moderate infection, and 12 mg/kg/day was needed to achieve AUC24/MIC ≥ 345 for severe infection. Lower weight and serum creatinine were associated with higher dose. Conclusion: Optimal doses based on the target C min were higher than that based on the PK/PD target. To achieve the C min and PK/PD targets simultaneously, a standard loading dose was adequate for moderate infection based on simulation, while dosing higher than standard doses were required in other situation. Further clinical studies with rich sampling from children is required to confirm our findings.

Project description: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.).

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

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

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