What is the optimal dose and duration of treatment with etoposide? II. Comparative pharmacokinetic study of three schedules: 1 x 100 mg, 2 x 50 mg, and 4 x 25 mg of oral etoposide daily for 21 days.

The large interpatient and intrapatient pharmacokinetic variability of oral etoposide is well known. We investigated whether dose fractionation would result in less variability. Fifteen patients (five in each etoposide schedule) were given either 100 mg once daily, 50 mg twice daily, or 25 mg four times daily for 21 days. On days 1, 8, and 15 blood samples were collected during 24 hours to measure plasma etoposide levels. Hematologic toxicity was determined by weekly leukocyte and platelet counts and expressed as the relative decrease in these parameters. Once-daily administration of etoposide 100 mg correlated with a significantly higher peak concentration than was observed with the other two schedules. The mean area under the concentration versus time curve (AUC) and mean time with a plasma etoposide concentration above 1 microgram/mL were similar with the three schedules. Peak plasma concentrations, AUCs, and times with plasma concentration above 1 micrograms/mL correlated significantly with the relative decrease in leukocyte but not platelet counts. Large interpatient and intrapatient variability of pharmacokinetic parameters was observed with all three schedules. These data do not support fractionating a daily 100-mg etoposide dose. Moreover, it does not appear useful to adjust oral etoposide doses based on pharmacokinetic data obtained once during a prolonged treatment period. Finally, adjusting oral etoposide doses based on hematologic toxicity seems advisable to decrease the interpatient variability of etoposide's pharmacokinetics.