PHARMACOKINETIC EVALUATION OF HIGH-DOSE ETOPOSIDE PHOSPHATE AFTER A 2-HOUR INFUSION IN PATIENTS WITH SOLID TUMORS

Etoposide phosphate, a water soluble prodrug of etoposide, was evaluat ed at levels potentially useful in transplantation settings in patient s with malignancies. For pharmacokinetic studies of etoposide phosphat e in this phase I study, 21 patients with solid tumors were treated wi th etoposide phosphate given as etoposide equivalents of 250, 500, 750 , 1000 and 1200 mg/m(2) infused over 2 h on days 1 and 2, and G-CSF 5 mu g/kg per day starting on day 3 until WBC was greater than or equal to 10000/mu l. Qualitative, quantitative, and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide p hosphate into etoposide by dephosphorylation occurred at all dosage le vels without indication of saturation of phosphatases. Plasma levels ( C-pmax) and area under the curve (AUC) of etoposide phosphate and etop oside demonstrated linear dose effects. For etoposide, plasma disposit ion demonstrated biphasic clearance, with mean T-1/2 alpha of 2.09 +/- 0.61 h, and T-1/2 beta of 5.83 +/- 1.71 h. An AUC as high as 1768.50 mu g.h/ml was observed at a dose of 1200 mg/m(2). The total body clear ance (TBC) showed an overall mean of 15.72 +/- 4.25 ml/min per m(2), a nd mean volume of distribution (V-Dss) of 5.64 +/- 1.06 l/m(2). The me an residual time (MRT) for etoposide was 6.24 +/- 1.61 h. In urine, et oposide but not etoposide phosphate, was identified with large quantit ative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide phosphate is converted into etop oside with the linear dose-related C-pmax and AUCs necessary for use o f this agent al the high dosage levels needed in transplantation proto cols. A comparison of pharmacokinetic parameters of high- dose etoposi de with the values observed in our study with etoposide phosphate reve aled comparable values for the clinically important C-pmax and AUCs, c learance, terminal T-1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefor e may offer the advantage of ease of administration.