After intravenous administration of 14C-etoposide (100-124 mg/m2), mean recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as etoposide; fecal recovery of radioactivity was 44% of the dose at 120 hours.
In children, approximately 55% of the dose of VePesid is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m2 or 35% of the total body clearance over a dose of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known in children.
Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. The hydroxy acid metabolite [4'-demethylepipodophyllic acid-9-(4,6-O-(R)-ethylidene-β-D-glucopyranoside)], formed by opening of the lactone ring, is found in the urine of adults and children. It is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14C-etoposide. In addition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.
In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration, and nonrenal clearance. Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC, and a lower volume of distribution at steady state (see PRECAUTIONS). Use of cisplatin therapy is associated with reduced total body clearance. In children, elevated serum SGPT levels are associated with reduced drug total body clearance. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children.
Although some minor differences in pharmacokinetic parameters between age and gender have been observed, these differences were not considered clinically significant.
Clinical Studies
A total of seven clinical trials with 365 patients treated (368 entered) provide the database for the human experience summarized in this insert. Five phase I trials eva luated etoposide phosphate given on a days 1, 3, and 5 or days 1 through 5 schedule. In two trials the drug was given over 5 minutes and in three over 30 minutes. The following table summarizes the doses, schedules, infusion times, and numbers of patients entered in the phase I experience.
Dose Escalation (Phase I) Trials of Etoposide Phosphate
Study
Schedule
Q 21 days
Infusion
Time
Dose Range
(mg/m2) Number of
Patients
Entered
002 Days 1-5 30 minutes 25-110 68
005 Days 1,3,5 30 minutes 50-175 39
006 Days 1-5 30 minutes 50-125 28
008 Days 1,3,5 5 minutes 50-200 36
009 Days 1-5 5 minutes 50-125 27
Two trials eva luated the pharmacokinetic equivalence of etoposide and etoposide phosphate. A phase I study (002) was expanded at the higher doses to compare the pharmacokinetic profile of etoposide following administration of etoposide or etoposide phosphate. Another multi-institutional trial (012) was conducted at a dose of 150 mg/m2 using a day 1, 3, and 5 schedule and a crossover design.
The seventh trial (011) was a randomized study in which patients w |
