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Pharmacokinetics of melphalan in children following high-dose intravenous injection
Insights
High-dose intravenous melphalan pharmacokinetics in children with neuroblastoma or Ewing's tumor were analyzed. While nitrobenzylpyridine assay correlated with plasma melphalan, high-pressure liquid chromatography remains the preferred method due to consistent bias in the NBP assay.
Area of Science:
- Pediatric Oncology
- Pharmacokinetics
- Analytical Chemistry
Background:
- High-dose intravenous melphalan is used in pediatric chemotherapy for neuroblastoma and Ewing's tumor.
- Accurate pharmacokinetic assessment is crucial for optimizing treatment efficacy and minimizing toxicity.
- Evaluating alternative, cost-effective analytical methods for melphalan monitoring is important.
Purpose of the Study:
- To characterize the pharmacokinetics of high-dose intravenous melphalan in pediatric cancer patients.
- To compare the accuracy and reliability of the nitrobenzylpyridine (NBP) assay with high-pressure liquid chromatography (HPLC) for measuring plasma melphalan concentrations.
- To determine if the NBP assay is a suitable alternative to HPLC for routine clinical monitoring.
Main Methods:
- Pharmacokinetic analysis of high-dose intravenous melphalan (140 or 220 mg m-2) in 10 children (aged 2.5-16 years).
- Simultaneous estimation of plasma melphalan concentration using both nitrobenzylpyridine (NBP) spectrophotometric assay and high-pressure liquid chromatography (HPLC) in five patients.
- Calculation of pharmacokinetic parameters including half-life, clearance, and volume of distribution.
Main Results:
- Pharmacokinetic parameters for melphalan in children (mean half-life 1.3 h, clearance 18.4 l x h-1 x m-2, volume of distribution 26.3 l x m-2) were comparable to adult values.
- No significant correlation was observed between pharmacokinetic parameters and patient age or glomerular filtration rate.
- The NBP assay showed consistent results and good correlation with HPLC but systematically underestimated plasma melphalan concentrations, indicating a bias.
Conclusions:
- The pharmacokinetic profile of high-dose intravenous melphalan in pediatric patients with neuroblastoma or Ewing's tumor is similar to that in adults.
- Despite good correlation, the nitrobenzylpyridine assay exhibits a consistent bias and is not a reliable substitute for HPLC in determining plasma melphalan pharmacokinetics.
- High-pressure liquid chromatography remains the gold standard for accurate plasma melphalan concentration measurement in this pediatric population.
Abstract:
The pharmacokinetics of high-dose IV melphalan (140 or 220 mg m-2) were studied after 12 administrations in 10 children (aged 2.5-16 years) undergoing chemotherapy for either neuroblastoma or Ewing's tumour. To assess whether a simpler and less expensive nitrobenzylpyridine (NBP) spectrophotometric assay for alkylating activity was a satisfactory alternative to high-pressure liquid chromatography (HPLC), the plasma melphalan concentration was estimated by both methods in five cases. Analysis of the disposition of melphalan gave a mean half-life of 1.3 +/- 1.0 (SD) h, clearance 18.4 +/- 9.4 l X h-1 X m-2, and apparent volume of distribution 26.3 +/- 18.0 l X m-2. These pharmacokinetic parameters were similar to those found in adults: no correlation was found between any parameter and age or glomerular filtration rate. NBP alkylating activity determinations yielded consistent results and good correlation with plasma melphalan concentration. However, concordance analysis indicated a consistent bias, the NBP assay always giving lower estimates of plasma melphalan concentration: HPLC assay therefore remains the method of choice for determining plasma melphalan pharmacokinetics.