PHASE-I AND PHARMACOKINETIC STUDY OF A WATER-SOLUBLE ETOPOSIDE PRODRUG, ETOPOSIDE PHOSPHATE (BMY-40481)

Etoposide phosphate is a water-soluble prodrug of etoposide. A phase I and pharmacokinetic study has been performed over the dose range 25-1 10 mg/m(2)/day for 5 days (etoposide equivalent doses). The maximum to lerated dose (MTD) was 110 mg/m(2)/day for 5 days every 3 weeks and th e dose-limiting toxicity was neutropenia. Other toxicities were mild, with the exception of 2 patients who displayed significant hypersensit ivity reactions. The etoposide phosphate:etoposide area under the plas ma concentration versus time curve (AUC) ratio was < 1% and the pharma cokinetic parameters for etoposide were within previously reported ran ges. Pharmacodynamic analyses demonstrated that etoposide AUC and base line white blood cell count were significant determinants of leucopeni a (model r(2) = 0.51).