PHASE I STUDY OF ETOPOSIDE PHOSPHATE (ETOPOPHOS) AS A 30-MINUTE INFUSION ON DAY-1, DAY-3, AND DAY-5

Etoposide phophate is a phosphate ester prodrug of etoposide designed to improve the pharmaceutical characteristics of the parent compound. A Phase I dose-escalating study of etoposide phosphate was conducted c oncurrently at two institutions to determine its toxicity, pharmacokin etics, and maximum tolerated dose, Etoposide phosphate was administere d i.v. for 30 min on days 1, 3, and 5 every 21 days or on recovery fro m toxicity, Cohorts of at least three patients received etoposide phos phate at dose levels from 50 mg/m(2) to 150 mg/m(2) expressed as molar equivalents of etoposide, Blood and urine samples were obtained from all patients during the first cycle of treatment and the concentration s of etoposide phosphate and etoposide were measured, Thirty-nine pati ents with documented cancers received a total of 75 cycles of etoposid e phosphate, The dose-limiting toxicity was myelosuppression which occ urred at the 150-mg/m(2) etoposide equivalent dose, Etoposide phosphat e was rapidly and extensively converted to etoposide, No measurable et oposide phosphate was detectable in the plasma by 15-60 min after the end of the infusion, The mean half-life of etoposide at the different dose levels ranged from 5.5 to 9.3 h. The pharmacokinetics of etoposid e, generated from etoposide phosphate, was linear over the dose range studied and was comparable to results reported in the literature for i .v. etoposide. In summary, i.v. etoposide phosphate is rapidly and ext ensively converted to etoposide, The maximum tolerated dose of etoposi de phosphate when given on days 1, 3, and 5 is 150 mg/m(2)/day. The do se-limiting toxicity is myelosuppression. The maximum tolerated dose a nd adverse event profile are consistent with those of etoposide.