Clinical relevance of etoposide (VP-16) pharmacokinetics in children and adults

A review of etoposide (VP-16) pharmacokinetics (PK) was undertaken to summarize the published data for pediatric patients in particular. While the PK of VP-16 in children has been studied only after intravenous (TV) administration, data from adults have been collected after IV, intraperitoneal, intrapleural, intraarterial and oral administration of the drug. As broad information about VP-16 PK in adults is available, the established pharmacokinetic profile is presented. The knowledge of VP-16 PK in children is scanty, although some studies include pediatric patients. While available results suggest that VP-16 distribution and elimination are independent of dose and schedule of administration, data detailing the influence of age on these parameters are still lacking. Moreover, studies of the degree of protein binding of VP-16 in children have not been published yet, although a recent study suggested a correlation between patient's age and the degree of plasma protein binding. A significant delay of elimination or increase in systemic toxicity after the administration of standard doses to patients with impaired renal function has not been documented yet, although renal clearance accounts for more than 35% of total body clearance in most studies. Recommendations for dose reductions in patients with impaired renal function are preliminary and should be the focus of,further investigations in all age groups. According to studies in adults, hepatobiliary clearance of VP-16 is of minor importance. Thus, recommendations to reduce the VP-16 dose in patients with liver dysfunction are not supported by changes in PK but by the genuine hepa totoxicity of the drug. Recent studies confirm that the liver cytochrome P450-3A4 is the dominant enzyme pathway of VP-16 metabolism. Four metabolites of VP-16 have been identified in vivo, two of which are cytotoxic in vitro. Pharmacokinetic data for these metabolites are not available. The interaction of VP-16 with other plasma components is of clinical importance. Studies in adults show an increased free fraction of VP-16 in patients with concomitant hyperbilirubinemia or hypoalbuminemia. In children and adults VP-16 elimination is accelerated following treatment with anticonvulsants. As the use of the commercially available preparation may cause dose-independent hyper sensitivity reactions secondary to its solvents, recent efforts have resulted in a hydrophilic derivative, VP-16 phosphate. First studies demonstrate unchanged PK and a lower incidence of hypersensitivity reactions than the parent compound. A first glance of the reviewed data describing VP-16 PK does not suggest major differences between juvenile and adult patients. Further studies on the issues mentioned should confirm these assumptions. These results could also contribute to the concept of drug monitoring as a suggested optimization of VP-16 tumoricidal efficacy.