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Cisplatin pharmacokinetics in children with cancer
B Peng1, M W English, A V Boddy
1Cancer Research Unit, Medical School, University of Newcastle upon Tyne, U.K.
Insights
Cisplatin pharmacokinetics in children show significant interpatient variability, suggesting current body surface area dosing may be inadequate for effective pediatric cancer treatment.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Clinical Chemistry
Background:
- Cisplatin is a vital chemotherapeutic agent for pediatric cancers.
- Limited pharmacokinetic data exist for cisplatin in children.
Purpose of the Study:
- To characterize cisplatin pharmacokinetics in pediatric cancer patients.
- To assess the adequacy of current body surface area-based dosing.
Main Methods:
- Studied 21 pediatric patients receiving 24-hour cisplatin infusions.
- Measured plasma and urine platinum levels using atomic absorption spectrophotometry.
- Analyzed pharmacokinetic parameters via non-compartmental and compartmental methods.
Main Results:
- Observed a 3-fold interpatient variability in free cisplatin exposure (AUC).
- Total free platinum clearance exceeded glomerular filtration rate (GFR).
- Renal clearance was not correlated with GFR, with limited urinary excretion.
Conclusions:
- Significant pharmacokinetic variability suggests body surface area dosing is not optimal for pediatric cisplatin therapy.
- Non-renal pathways likely contribute significantly to cisplatin clearance in children.
- Further research is needed to optimize dosing strategies for improved pediatric cancer treatment outcomes.
Abstract:
Cisplatin is an important drug in the treatment of a number of paediatric cancers yet, despite widespread use, there are only very limited data on the pharmacokinetics of the drug in children. Cisplatin pharmacokinetics were studied in 21 patients following a 24 h infusion of 50-120 mg/m2 cisplatin. Total and free platinum (Pt) levels in plasma and Pt in urine, were measured by atomic absorption spectrophotometry. Pharmacokinetic parameters were determined by non-compartmental and compartmental analyses. There was 3-fold interpatient variability in free drug exposure (area under the plasma concentration versus time curve--AUC) for a given surface area-based dose of cisplatin. The mean (+/- SD) pharmacokinetic parameters for free Pt were: AUC 0.47 +/- 0.13 mg/ml.min/100 mg/m2, Vdss 12.5 +/- 2.7 l/m2, t1/2 39 +/- 9 min, Ke 0.019 +/- 0.006 min-1, Clrenal 62 ml/min/m2, Cltotal 233 +/- 455 ml/min/m2, Cpss 0.31 +/- 0.09 microgram/ml. The total free Pt clearance was 1.5-5.8-fold higher (3.4 +/- 1.0) than the glomerular filtration rate (GFR). The renal clearance of cisplatin was not related to GFR and cisplatin was subject to only limited urinary excretion (27% administered dose 0-48 h), indicating that there are other important pathways of clearance beside renal elimination. Patient and treatment heterogeneity precluded the investigation of pharmacokinetic-pharmacodynamic relationships; however, the degree of interpatient pharmacokinetic variability observed suggests that body surface area-based dosing of cisplatin in children is not satisfactory.