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Etoposide pharmacokinetics in children: the development and prospective validation of a dosing equation
S P Lowis1, A D Pearson, D R Newell
1Department of Child Health, University of Newcastle upon Tyne, United Kingdom.
Insights
Pharmacokinetic monitoring of etoposide in children can be improved using a new equation. This method accurately predicts drug exposure, reducing variability and preventing over- or underexposure compared to standard body surface area dosing.
Area of Science:
- Pediatric Oncology
- Pharmacokinetics
- Drug Metabolism and Disposition
Background:
- Etoposide is a crucial chemotherapy agent used in pediatric oncology.
- Standard dosing based on body surface area (BSA) can lead to significant inter-patient variability in etoposide exposure.
- Understanding etoposide pharmacokinetics in children is essential for optimizing treatment efficacy and minimizing toxicity.
Purpose of the Study:
- To develop and validate a pharmacokinetic monitoring equation for etoposide in children.
- To assess the accuracy of the developed equation in predicting etoposide area under the concentration-time curve (AUC).
- To compare the predictive accuracy of the new equation with BSA-based dosing.
Main Methods:
- Pharmacokinetic data from 33 children treated with etoposide were analyzed.
- A predictive equation for etoposide AUC was developed using data from 20 patients and validated in 13 others.
- The equation incorporates the 51Cr-EDTA elimination constant and a single blood sample.
Main Results:
- The developed pharmacokinetic monitoring equation accurately predicted etoposide AUC with minimal bias and small predictive error.
- Variability in etoposide AUC was significantly higher with BSA-based dosing compared to the monitoring equation.
- The equation proved effective in identifying patients at risk of over- or underexposure.
Conclusions:
- A novel pharmacokinetic monitoring equation enables accurate prediction of etoposide AUC in children.
- This approach significantly reduces inter-individual variability in drug exposure compared to BSA-based dosing.
- Pharmacokinetic monitoring facilitates personalized etoposide dose adjustments, improving therapeutic outcomes.
Abstract:
Pharmacokinetic studies of etoposide administered at 100-200 mg/m2 to 33 children are described. Twenty-seven studies were performed in children aged < 10 years. Repeat studies were performed in 11 patients. Median pharmacokinetic parameters were as follows: plasma clearance, 26 ml/min/m2; volume of distribution, 4.9 liters/m2; area under the etoposide plasma concentration-time curve (AUC), 3.9 mg/ml x min per 100 mg/m2. Interindividual variability in pharmacokinetic parameters was large (coefficient of variation (CV) = 30, 28, and 27%, respectively) in comparison with intraindividual variability (CV = 12, 14, and 12%, respectively). Variability in AUC was much greater in those patients treated with 150-200 mg/m2 etoposide than with 100 mg/m2 (CV, 35 versus 13%) and was related to variability in renal function and prior exposure to cisplatin. Data from the first 20 studies were used to develop pharmacokinetic monitoring equations which were validated in a further 13 patients. The most accurate equation relies upon the elimination constant of 51Cr-EDTA and a single blood specimen taken at the end of the etoposide infusion. [formula: see text] where K = 51Cr-EDTA elimination rate constant. This equation showed no significant bias, and the predictive error was small with respect to AUC calculated according to a two-compartment model. Predictive error did not increase with increasing AUC, whereas a marked increase in predictive error was seen for dosing according to body surface area. Dosing according to body surface area alone led to marked over- or underexposure to etoposide in 8 patients. Pharmacokinetic monitoring using the equation described would have identified these patients and permitted dose modification. This approach provides an accurate means of monitoring etoposide AUC for administration times of 1-4 h without the need for detailed pharmacokinetic sampling. It will allow a significant reduction in the variability of exposure seen with surface area-based dosing.