ute infusion time, the etoposide mean ± S.D. AUC values (normalized to the 100 mg/m2 dose) were 96.1 ± 22.6 µg•hr/mL and 86.5 ± 25.8 µg•hr/mL, respectively; the corresponding mean ± S.D. Cmax values (normalized to the 100 mg/m2 dose) were 20.1 ± 4.1 µg/mL and 19.0 ± 5.1 µg/mL, respectively. The point estimate (90% confidence interval) for the bioavailability of etoposide from Etopophos, relative to VePesid, was 113% (107%, 119%) for AUC and 107% (101%, 113%) for Cmax indicating bioequivalence. Results from both studies demonstrated no statistically significant differences in the AUC and Cmax parameters for etoposide when administered as Etopophos or VePesid. In addition, in the latter study, there were no statistically significant differences in the pharmacodynamic parameters (hematologic toxicity) after administration of Etopophos or VePesid. Following VePesid administration, the mean nadir values (expressed as percent decrease from baseline) for leukocytes, granulocytes, hemoglobin, and thrombocytes were 67.2 ± 17.0%, 84.1 ± 14.6%, 22.6 ± 9.8%, and 46.4 ± 21.9%, respectively; the corresponding values after administration of Etopophos were 67.3 ± 14.2%, 81.0 ± 16.5%, 21.4 ± 9.9%, and 44.1 ± 20.7%, respectively.
Because of the similarity of pharmacokinetics and pharmacodynamics of etoposide after administration of either Etopophos or VePesid, the following information on VePesid should be considered:
VePesid Pharmacokinetics
On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min or 16 to 36 mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a range 100 to 600 mg/m2. Over the same dose range, the AUC and the Cmax values increase linearly with dose. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m2 for 4 to 5 days. After intravenous infusion the Cmax and AUC values exhibit marked intra- and inter-subject variability.
The mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to 17 L/m2. Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. In vitro, etoposide is highly protein bound (97%) to human plasma proteins. An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children. In a study determining the effect of other therapeutic agents on the in vitro binding of carbon-14 labeled etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations achieved in vivo.
Etoposide binding ratio correlates directly with serum albumin in patients with cancer and in normal volunteers. The unbound fraction of etoposide significantly correlated with bilirubin in a population of cancer patients. Data have suggested a significant inverse correlation between serum albumin concentration and free fraction of etoposide (see PRECAUTIONS).
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