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 × 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. 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.
S. P. L. and M. C. are supported by the North of England Children's Cancer Research Fund. Financial support was provided by Leukemia Research Fund and the North of England Cancer Research Campaign.