Pharmacology: Pharmacodynamics: Etoposide is a semi synthetic derivative of podophyllotoxin used in the treatment of certain neoplastic disease.
Mechanism of Action/Effect: The exact mechanism of Etoposide's antineoplastic effect is unknown. Etoposide is a topoisomerase II inhibitor. It seems to act at the premitotic stage of cell division to inhibit DNA synthesis; it is cell cycle dependent and phase specific, with maximum effect on the S and G 2 phase of division.
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 36mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a range 100-600 mg/m2. Over the same dose range, the areas under the plasma concentration vs. time curves (AUC) and the maximum plasma concentration (Cmax) values increase linearly with dose. Etoposide dose not accumulate in the plasma following daily administration of 100 mg/m2 for 4 to 5 days.
The mean volumes of distribution at steady 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. 2,3 Data have suggested a significant inverse correlation between serum albumin concentration and free fraction of Etoposide.
Metabolism and Excretion: There is no evidence of a first-pass effect for Etoposide. For example, no correlation exists between the absolute oral bioavailability of Etoposide capsules and non renal clearance. No evidence exists for any other differences in Etoposide metabolism and excretion after administration of oral capsules as compared to intravenous infusion.
In children, approximately 55% of the dose is excreted in the urine as Etoposide in 24 hours. The mean renal clearance of Etoposide is 7 to 10 mL/min/m2 or about 35% of the total body clearance over a dose range of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both renal and non renal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma Etoposide clearance is not known.