PROBLEM: The interindividual variation of etoposide pharmacokinetics under different therapeutic schedules and the rationale of dose reduction in young children and newborns were investigated in the present study. PATIENTS AND METHODS: We evaluated pharmacokinetic parameters during short-term infusion in 21 therapy cycles (18 children) on different therapeutic schedules (66-200 mg/m2). In 33 patients state levels (Css) during continuous infusion of 125 mg/m2/96 h were analyzed by an HPLC-method. RESULTS: During short-term infusion half-life (3.3 +/- 0.7 h) and total body clearance (26 +/- 6 ml/min/m2) showed a relatively narrow range. Calculation of the area under the curve was standardized to a dosage of 100 mg/m2 (AUC/[100 mg/m2]). The AUC then was 68 +/- 17 (micrograms.h/ml)/(100 mg/m2) with a coefficient of variation of 25%. In the subgroup of 10 patients who received 150 mg/m2 the AUC was 106 +/- 15 micrograms.h/ml with only 14% coefficient of variation. In children < 2 years, pharmacokinetic parameters were within the normal range. Calculation of the doses the short-term infusion per kg resulted in a dose reduction or 31% (mean, n = 5) and in 22% (mean) lower AUC's. With continuous infusion of 125 mg/m2 etoposide the interpatient variability was greater with a 33% coefficient of variation of the Css (4.4 +/- 1.4 micrograms/ml; n = 24). Calculation of the doses per kg (age < 1 year) or 2/3.kg resulted in reduced Css. Standardization of these levels showed Css (125 mg/m2) of 4.6 +/- 1.4 micrograms/ml and a coefficient of variation of 31%. CONCLUSIONS: Interpatient variability of etoposide pharmacokinetics at least during short-term infusion is limited. Dose reduction is not substantiated in children < 2 years by our pharmacokinetic data.
PROBLEM: The interindividual variation of etoposide pharmacokinetics under different therapeutic schedules and the rationale of dose reduction in young children and newborns were investigated in the present study. PATIENTS AND METHODS: We evaluated pharmacokinetic parameters during short-term infusion in 21 therapy cycles (18 children) on different therapeutic schedules (66-200 mg/m2). In 33 patients state levels (Css) during continuous infusion of 125 mg/m2/96 h were analyzed by an HPLC-method. RESULTS: During short-term infusion half-life (3.3 +/- 0.7 h) and total body clearance (26 +/- 6 ml/min/m2) showed a relatively narrow range. Calculation of the area under the curve was standardized to a dosage of 100 mg/m2 (AUC/[100 mg/m2]). The AUC then was 68 +/- 17 (micrograms.h/ml)/(100 mg/m2) with a coefficient of variation of 25%. In the subgroup of 10 patients who received 150 mg/m2 the AUC was 106 +/- 15 micrograms.h/ml with only 14% coefficient of variation. In children < 2 years, pharmacokinetic parameters were within the normal range. Calculation of the doses the short-term infusion per kg resulted in a dose reduction or 31% (mean, n = 5) and in 22% (mean) lower AUC's. With continuous infusion of 125 mg/m2 etoposide the interpatient variability was greater with a 33% coefficient of variation of the Css (4.4 +/- 1.4 micrograms/ml; n = 24). Calculation of the doses per kg (age < 1 year) or 2/3.kg resulted in reduced Css. Standardization of these levels showed Css (125 mg/m2) of 4.6 +/- 1.4 micrograms/ml and a coefficient of variation of 31%. CONCLUSIONS: Interpatient variability of etoposide pharmacokinetics at least during short-term infusion is limited. Dose reduction is not substantiated in children < 2 years by our pharmacokinetic data.