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Population Pharmacokinetics and Dosage Optimization of Teicoplanin in Children With Different Renal Functions.

ABSTRACT: Objective:The purposes of our study were to investigate the population pharmacokinetics of teicoplanin in Chinese children with different renal functions and to propose the appropriate dosing regimen for these pediatric patients. Methods:We performed a prospective pharmacokinetic research on children aged 0-10 years, with different renal functions. The population pharmacokinetics model of teicoplanin was developed using NLME program. The individualized optimal dosage regimen was proposed on the basis of the obtained population pharmacokinetics parameters. Results:To achieve the target trough level of 10-30 mg/L, optimal dosing regimen for children with different renal functions are predicted as follows based on the population PK simulations: children with moderate renal insufficiency need three loading doses of 6 mg/kg q12h followed by a maintenance dose of 5 mg/kg qd; children with mild renal insufficiency require three loading doses of 12 mg/kg q12h followed by a maintenance dose of 8 mg/kg qd; children with normal or augmented renal function should be given three loading doses of 12 mg/kg q12h followed by a maintenance doses of 10 mg/kg qd. Conclusion:The first study on the population pharmacokinetics of teicoplanin in Chinese children with different renal functions was performed. Individualized dosing regimen was recommended for different renal function groups based on population PK model prediction.

SUBMITTER: Gao L

PROVIDER: S-EPMC7214819 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Population Pharmacokinetics and Dosage Optimization of Teicoplanin in Children With Different Renal Functions.

Gao Liuliu L Xu Hua H Ye Qi Q Li Sichan S Wang Jun J Mei Yan Y Niu Changhe C Kang Ting T Chen Chen C Wang Yang Y

Frontiers in pharmacology 20200505

<h4>Objective</h4>The purposes of our study were to investigate the population pharmacokinetics of teicoplanin in Chinese children with different renal functions and to propose the appropriate dosing regimen for these pediatric patients.<h4>Methods</h4>We performed a prospective pharmacokinetic research on children aged 0-10 years, with different renal functions. The population pharmacokinetics model of teicoplanin was developed using NLME program. The individualized optimal dosage regimen was p ...[more]

PMID: 32431611

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Project description:Teicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. The linear model best accounted for the observed data and was subsequently chosen for Monte Carlo simulations. The PK parameter medians/means (standard deviation [SD]) were as follows: CL, [0.019/0.023 (0.01)] × weight liters/h/kg of body weight; volume, 2.282/4.138 liters (4.14 liters); first-order rate constant from the central to peripheral compartment (Kcp), 0.474/3.876 h(-1) (8.16 h(-1)); and first-order rate constant from peripheral to central compartment (Kpc), 0.292/3.994 h(-1) (8.93 h(-1)). The percentage of patients with a minimum concentration of drug in serum (Cmin) of <10 mg/liter was 53.85%. The median/mean (SD) total population area under the concentration-time curve (AUC) was 619/527.05 mg · h/liter (166.03 mg · h/liter). Based on Monte Carlo simulations, only 30.04% (median AUC, 507.04 mg · h/liter), 44.88% (494.1 mg · h/liter), and 60.54% (452.03 mg · h/liter) of patients weighing 50, 25, and 10 kg, respectively, attained trough concentrations of >10 mg/liter by day 4 of treatment. The teicoplanin population PK is highly variable in children, with a wider AUC distribution spread than for adults. Therapeutic drug monitoring should be a routine requirement to minimize suboptimal concentrations. (This trial has been registered in the European Clinical Trials Database Registry [EudraCT] under registration number 2012-005738-12.).

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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Population Pharmacokinetics and Dosage Optimization of Teicoplanin in Children With Different Renal Functions.

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Population Pharmacokinetics and Dosage Optimization of Teicoplanin in Children With Different Renal Functions.

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