Pharmacokinetic optimisation of treatment with oral etoposide

Giuseppe Toffoli, Giuseppe Corona, Barbara Basso, Mauro Boiocchi

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Etoposide is a derivative of podophyllotoxin widely used in the treatment of several neoplasms, including small cell lung cancer, germ cell tumours and non-Hodgkin's lymphomas. Prolonged administration of etoposide aims for continuous inhibition of topoisomerase II, the intracellular target of etoposide, thus preventing tumour cells from repairing DNA breaks. However, the clinical advantages of extended schedules as compared with conventional short-term infusions remain unclear. Oral administration of etoposide represents the most feasible and economic strategy to maintain effective concentrations of drug for extended times. Nevertheless, the efficacy of oral etoposide therapy is contingent on circumventing pharmacokinetic limitations, mainly low and variable bioavailability. Inhibition of small bowel and hepatic metabolism of etoposide with specific cytochrome P450 inhibitors or inhibition of the intestinal P-glycoprotein efflux pump have been attempted to increase the bioavailability of oral etoposide, but the best results were obtained with daily oral administration of low etoposide doses (50-100 mg/ day for 14-21 days). Saturable absorption of etoposide was reported for doses greater than 200 mg/day, whereas lower doses were associated with increased bioavailability, although they were characterised by high inter- and intrapatient variability. Pharmacokinetic parameters such as plasma trough concentration between two oral administrations (C24,trough), drug exposure time above a threshold value and area under the plasma concentration-time curve have been correlated with the pharmacodynamic effect of oral etoposide. Pharmacokinetic- pharmacodynamic relationships indicate that severe toxicity is avoided when peak plasma concentrations do not exceed 3-5 mg/L and C24,trough is under the threshold limit of 0.3 mg/ L. To maintain effective etoposide plasma concentrations during prolonged oral administration, pharmacokinetic variability must be monitored in each patient, taking account of factors from many pharmacokinetic studies of etoposide, including absorption, distribution, protein binding, metabolism and elimination. Dosage reduction is generally useful to avoid haematological toxicity in patients with renal dysfunction (creatinine clearance

Original languageEnglish
Pages (from-to)441-466
Number of pages26
JournalClinical Pharmacokinetics
Issue number7
Publication statusPublished - 2004

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)


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