Etoposide phosphate (EP) is a water-soluble derivative of
etoposide (VP-16), a semisynthetic
podophyllotoxin which is useful in the treatment of a wide variety of
hematological malignancies and solid
tumors. Because
etoposide is poorly water soluble, it must be dissolved in a variety of organic
solvents and given in relatively large volumes of saline. EP is rapidly converted to the parent
drug in vivo and has been shown to be active in animal studies. We performed a phase I pharmacokinetic study in 27 patients. Three patients each received an
etoposide-equivalent dose of 50 or 75 mg/m2 each day by i.v. bolus (5 min) daily for 5 days and 21 patients received a dose equivalent to 100 mg/m2 of
etoposide each day for 5 days. Non-compartmental pharmacokinetic data were obtained for 22 of the patients. As with previous studies, EP behaves as a
prodrug of
etoposide. The Cmax (25.3-42.5 micrograms/ml) increased linearly, while AUCinf (75.8-156 h micrograms/ml) of
etoposide increased proportionately with dose (50-100 mg/m2 of
etoposide equivalents). Time to achieve Cmax corresponded to the end of the 5 min injection, indicating a rapid formation of
etoposide from EP. Mean
etoposide phosphate/
etoposide Cmax and AUCinf ratios were 0.08 or less and 0.003, respectively, indicating that the major circulating moiety in plasma was
etoposide. Parameters such as MRT, T1/2, CL/F, CLR, VSS/F and %UR were dose independent. The toxicities of EP were virtually identical to those seen with
etoposide, with dose-related myelosuppression,
alopecia and
stomatitis. Severe
neutropenia was the dose-limiting toxicity. No significant problems with
hypotension or
allergic reactions were observed. No problems, difficulties or complications were observed as a result of bolus (5 min) administration. On the basis of phase I toxicity data, we recommend an
etoposide equivalent starting dose of 100 mg/m2/day for 5 days in previously untreated patients who have an excellent performance status. In patients who have had one or more prior
chemotherapy regimens, extensive prior
radiation therapy or moderately impaired performance status, we recommend an
etoposide phosphate starting dose of 75 mg/m2/day for 5 days with courses repeated at 3 week intervals.