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

Abstract.

Purpose: To compare etoposide pharmacokinetics following administration of high-dose etoposide and etoposide phosphate, a water-soluble prodrug of etoposide. Bioequivalence was assessed using a two-treatment randomized crossover design. Methods: Ten patients with high-risk or relapsed lymphoma were treated with a sequential high-dose chemotherapy. They were randomized to receive either 3×400 mg/m² etoposide or an equimolar amount of etoposide phosphate (as 1-h infusions on three consecutive days) in the first course and the alternative drug in the second course. Serial plasma and ultrafiltered plasma samples were collected and analysed for etoposide by a reversed-phase HPLC method with UV and electrochemical detection. Pharmacokinetic parameters were estimated using a two-compartment model. Bioequivalence was assessed calculating the 90% confidence intervals (CI) for the ratios of the geometric means of AUC_0-∞ and additionally of C_max of etoposide derived from etoposide phosphate relative to etoposide in plasma and ultrafiltered plasma as point estimates (level of significance α<0.05). Results: Pharmacokinetic parameters of etoposide were comparable in both treatment arms except that terminal half-life was significantly shorter and apparent V_ss in ultrafiltered plasma was significantly larger following administration of the prodrug. The point estimates for AUC_0-∞ 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 the range from 80% to 125% where bioequivalence can be assumed. The point estimates of C_max on day 3 of chemotherapy were 96.5% and 81.7% in plasma and ultrafiltrate with the 90% CI in ultrafiltered plasma being out of the range from 80% to 125%. Conclusion: With respect to total drug exposure, represented by AUC_0-∞, high-dose etoposide phosphate is bioequivalent to high-dose etoposide.