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Kaul S , Igwemezie LN , Stewart DJ , Fields SZ , Kosty M , Levithan N , Bukowski R , Gandara D , Goss G , Odwyer P , Schacter LP , Barbhaiya RH
Pharmacokinetics and Bioequivalence of Etoposide Following Intravenous Administration of Etoposide Phosphate and Etoposide in Patients with Solid Tumors
Journal of Clinical Oncology. 1995 Nov;13(11) :2835-2841
PMID: ISI:A1995TC98600023   
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Abstract
Purpose: To assess the pharmacokinetics and bioequivalence of etoposide following intravenous (IV) administration of etoposide phosphate (Etopophos; Bristol-Myers Squibb, princeton, NJ), a prodrug of etoposide, and VePesid (Bristol- Myers Squibb). Patients and Methods: Forty-nine solid tumor patients were randomized to receive Etopophos or VePesid on day 1 of a day-1,3,5 schedule of treatment. The alternate drug was given on day 3 and repeated on day 5. The dose, 150 mg/m(2) of etoposide equivalent, was administered by constant rare infusion over 3.5 hours. The plasma concentrations of etoposide phosphate and etoposide were determined using validated high- performance liquid chromatography (HPLC) assays. Pharmacokinetic parameters were calculated by a noncompartmental method. Etopophos was considered to be bioequivalent to VePesid if the 90% confidence limits for the differences in mean maximum concentration (C-max) and AUC(inf) of etoposide were contained within 80% to 125% for the log- transformed data. Results: Forty-one patients were assessable for pharmacokinetics and bioequivalence assessment. Following IV administration, etoposide phosphate was rapidly and extensively converted to etoposide in systemic circulation, resulting in insufficient data to estimate its pharmacokinetics. The mean bioavailability of etoposide from Etopophos, relative to VePesid, was 103% (90% confidence interval, 99% to 106%) based on C-max, and 107% (90 confidence interval, 105% to 110%) based on area under the concentration versus rime curve from zero to infinity (AUC(inf)) values. Mean terminal elimination half-life (t(1/2)), steady-state volume of distribution (V-SS), and total systemic clearance (CL) values of etoposide were approximately 7 hours, 7 L/m(2), and 17 mL/min/m(2) after Etopophos and VePesid treatments, respectively. The main toxicity observed was myelosuppression, characterized by leukopenia and neutropenia. Conclusion: With respect to plasma levels of etoposide, IV Etopophos is bioequivalent to IV VePesid. (C) 1995 by American Society of Clinical Oncology.
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Times Cited: 16 Article TC986 J CLIN ONCOL