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Population pharmacokinetics of amphotericin B in children with malignant diseases
C E Nath1, A J McLachlan, P J Shaw
1Department of Biochemistry, The Children's Hospital at Westmead, NSW, Australia. christan@chw.edu.au
Insights
A population pharmacokinetic model for amphotericin B (AmB) was developed in pediatric cancer patients. This model accurately predicts AmB concentrations, aiding in safe and effective dosing for children.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Clinical Pharmacy
Background:
- Amphotericin B (AmB) is a critical antifungal agent used in pediatric patients with malignant diseases.
- Optimizing AmB dosing is essential for efficacy and minimizing toxicity in this vulnerable population.
- Existing pharmacokinetic data in children with cancer is limited.
Purpose of the Study:
- To develop a robust population pharmacokinetic (PopPK) model for AmB in children undergoing cancer treatment.
- To identify key covariates influencing AmB pharmacokinetics, such as weight and dose formulation.
- To validate the predictive performance of the developed PopPK model.
Main Methods:
- A two-compartment PopPK model was constructed using concentration-time data from 57 pediatric patients.
- The P-Pharm software (version 1.5) was utilized for parameter estimation and covariate analysis.
- Model performance was assessed using an independent validation group of 26 children.
Main Results:
- Population pharmacokinetic parameters for clearance (CL) and volume of distribution (V) were estimated.
- Significant covariate relationships were identified: CL was influenced by weight and dose formulation, while V was affected by weight.
- The covariate model demonstrated unbiased and precise predictions in the validation cohort.
Conclusions:
- A validated population pharmacokinetic model for AmB in pediatric cancer patients has been successfully developed.
- This model provides a foundation for optimizing AmB dosing strategies in this population.
- Future application of this model can inform the development of precise dosing guidelines for safe and effective AmB therapy.
Aims:
To construct a population pharmacokinetic model for the antifungal agent, amphotericin B (AmB), in children with malignant diseases.
Methods:
A two compartment population pharmacokinetic model for AmB was developed using concentration-time data from 57 children aged between 9 months and 16 years who had received 1 mg kg(-1) day(-1) doses in either dextrose (doseform=1) or lipid emulsion (doseform=2). P-Pharm (version 1.5) was used to estimate the basic population parameters, to identify covariates with significant relationships with the pharmacokinetic parameters and to construct a Covariate model. The predictive performance of the Covariate model was assessed in an independent group of 26 children (the validation group).
Results:
The Covariate model had population mean estimates for clearance (CL), volume of distribution into the central compartment (V) and the distributional rate constants (k12 and k21) of 0.88 l h(-1), 9.97 l, 0.27 h(-1) and 0.16 h(-1), respectively, and the intersubject variability of these parameters was 19%, 49%, 55% and 48%, respectively. The following covariate relationships were identified: CL (l h(-1)) = 0.053 + 0.0456 weight (0.75) (kg) + 0.242 doseform and V (l) = 7.11 + 0.107 weight (kg). Our Covariate model provided unbiased and precise predictions of AmB concentrations in the validation group of children: the mean prediction error was 0.0089 mg l(-1) (95% confidence interval: -0.0075, 0.0252 mg l(-1)) and the root mean square prediction error was 0.1245 mg l(-1) (95% confidence interval: 0.1131, 0.1349 mg l(-1)).
Conclusions:
A valid population pharmacokinetic model for AmB has been developed and may now be used in conjunction with AmB toxicity and efficacy data to develop dosing guidelines for safe and effective AmB therapy in children with malignancy.