Etoposide - How It Works
Clinical pharmacology details from the US FDA-approved label: how Etoposide works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
CLINICAL PHARMACOLOGY Etoposide Injection has been shown to cause metaphase arrest in chick fibroblasts.
Its main effect, however, appears to be at the G 2 portion of the cell cycle in mammalian cells.
Two different dose-dependent responses are seen.
At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is observed.
At low concentrations (0.3 to 10 mcg/mL), cells are inhibited from entering prophase.
It does not interfere with microtubular assembly.
The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA topoisomerase II or the formation of free radicals.
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/m 2 and, like the terminal elimination half-life, are independent of dose over a range 100 to 600 mg/m 2 .
Over the same dose range, the areas under the plasma concentration vs time curves (AUC) and the maximum plasma concentration (C max ) values increase linearly with dose.
Etoposide does not accumulate in the plasma following daily administration of 100 mg/m 2 for 4 to 5 days.
The mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to 17 L/m 2 .
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.
Pharmacokinetics
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/m 2 and, like the terminal elimination half-life, are independent of dose over a range 100 to 600 mg/m 2 . Over the same dose range, the areas under the plasma concentration vs time curves (AUC) and the maximum plasma concentration (C max ) values increase linearly with dose. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m 2 for 4 to 5 days. The mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to 17 L/m 2 . 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-bo