CLINICAL AND PHARMACOKINETIC OVERVIEW OF PARENTERAL ETOPOSIDE PHOSPHATE

Etoposide phosphate (Etopophos, BMY-40481) is a water-soluble derivati ve of the widely used podophyllotoxin etoposide (VP-16). The phosphate ester renders the compound water-soluble, eliminating the need for fo rmulation in polysorbate (Tween) 80, ethanol, and polyethylene glycol. As a result the compound can be given at high concentrations and as a bolus. In animals and in vitro, etoposide phosphate (EP) is rapidly a nd completely converted to VP-16. Clinical development of the i.v. for mulation has focused on the identification of the maximum tolerated do se (MTD) and pharmacokinetic characteristics of the drug using a 5 dai ly dose schedule and a days 1, 3, and 5 schedule, with the drug being given over 30 or 5 (bolus) min. Myelosuppression was dose-limiting. Da ta from these trials show the rapid and complete conversion of EP to V P-16, a pharmacokinetic/pharmacodynamic relationship for myelosuppress ion and exposure to VP-16, and an MTD of 100 and 150 mg/m(2) (molar eq uivalent to VP-16) when EP is given daily for 5 days and on days 1, 3, and 5. respectively. A formal randomized trial has been conducted to show the pharmacokinetic comparability of EP and VP-16. In this trial, exposure to VP-16 was the same after the parenteral administration of equimolar doses of EP or VP-16. The feasibility of bolus dosing and t reatment at high concentrations has been demonstrated, with no effects on the cardiovascular system being noted. Parenteral EP is pharmacoki netically and biologically equivalent to VP-16 and has the advantages of the elimination of potentially toxic excipients; more convenient ad ministration; and ability to be given as a bolus, at high concentratio ns, and as a continuous infusion.