Bioequivalence investigation of high-dose etoposide and etoposide phosphate in lymphoma patients

Purpose: To compare etoposide pharmacokinetics following administration of high-dose etoposide and etoposide phosphate, a water-soluble prodrug of eto poside. Bioequivalence was assessed using a two-treatment randomized crosso ver design. Methods: Ten patients with high-risk or relapsed lymphoma were treated with a sequential high-dose chemotherapy. They were randomized to r eceive either 3x400 mg/m(2) etoposide or an equimolar amount of etoposide p hosphate (as I-h infusions on three consecutive days) in the first course a nd the alternative drug in the second course. Serial plasma and ultrafilter ed plasma samples were collected and analysed for etoposide by a reversed-p hase HPLC method with UV and electrochemical detection. Pharmacokinetic par ameters were estimated using a two-compartment model. Bioequivalence was as sessed calculating the 90% confidence intervals (CI) for the ratios of the geometric means of AUC(0-infinity) and additionally Of Cma, of etoposide de rived from etoposide phosphate relative to etoposide in plasma and ultrafil tered plasma as point estimates (level of significance alpha < 0.05). Resul ts: Pharmacokinetic parameters of etoposide were comparable in both treatme nt arms except that terminal half-life was significantly shorter and appare nt V-ss in ultrafiltered plasma was significantly larger following administ ration of the prodrug. The point estimates for AUC(0-infinity) of etoposide derived from etoposide phosphate relative to etoposide were 102.9% and 88. 4% for plasma and ultrafiltered plasma, respectively. The 90% CIs were in t he range from 80% to 125% where bioequivalence can be assumed. The point es timates of C-max on day 3 of chemotherapy were 96.5% and 81.7% in plasma an d ultraflitrate with the 90% Cl in ultrafiltered plasma being out of the ra nge from 80% to 125%. Conclusion: With respect to total drug exposure, repr esented by AUC(0-infinity), high-dose etoposide phosphate is bioequivalent to high-dose etoposide.