The clinical pharmacology of etoposide

Etoposide, a semisynthetic derivative of podophyllotoxin, is increasingly used to treat cancer. Etoposide is a phase-specific, cytotoxic drug acting in the late S and early G2 phases of the cell cycle. It appears to cause breaks in DNA by either an interaction with DNA-topoisomerase II or the formation of free radicals. Most studies show a biexponential decay after the intravenous (IV) administration of etoposide. The peak plasma concentrations of drug and the area under the concentration versus time curve (AUC) are linearly related to the IV dose. Considerable interpatient variability of pharmacokinetic variables exists after IV etoposide. Various metabolites of etoposide have been identified, but their detection and quantitation are disputed. Approximately 30% to 70% of an etoposide dose is excreted. The bioavailability of oral etoposide is approximately 50%, but its absorption is not linear with increasing doses within the range in clinical use. Considerable interpatient and intrapatient variability exists in the pharmacokinetics of oral etoposide. There is no evidence of etoposide accumulation after multiple consecutive doses by either the IV or oral route. The exact roles of the liver and kidney in metabolism and excretion of etoposide are uncertain. Etoposide has been shown to be a highly schedule-dependent drug in clinical studies. This, together with the phase-specific action of etoposide and its increasingly widespread use in treating cancer, makes the clinical pharmacology of this drug of great clinical importance.