Disposition of total and unbound etoposide following high-dose therapy

Total and unbound etoposide pharmacokinetics were studied in 16 adult patients (median age, 34 years; range, 18-61 years) undergoing autologous bone marrow transplantation for advanced lymphoma after receiving high-dose etoposide (35-60 mg/kg) as a single intravenous infusion. Pretreatment values for mean serum albumin and total bilirubin were 3.0 +/- 0.4 g/dl and 0.5 +/- 0.4 mg/dl, respectively. Etoposide plasma concentrations and protein binding (%unbound) were determined by high-performance liquid chromatography (HPLC) and equilibrium dialysis, respectively. Pharmacokinetic parameters for unbound and total etoposide were calculated by nonlinear regression analysis using a two-compartment model. The mean (+/- SD) parameters for total etoposide included: clearance (CL), 31.8 +/- 17.7 ml min-1 m-2; volume of distribution (Vss), 11.5 +/- 5.9 l/m2, and terminal half-life (t1/2 beta), 7.2 +/- 3.7 h. Mean unbound CL was 209.6 +/- 62.7 ml min-1 m-2 and %unbound was 16% +/- 5%. The mean etoposide %unbound was inversely related to serum albumin (r2 = 0.45, P = 0.0043). The mean %unbound at the end of the etoposide infusion was higher than that at the lowest measured concentration (21% vs 13%, respectively; P = 0.017), suggesting that concentration-dependent binding may occur after high etoposide doses. The median total CL was higher in patients with serum albumin concentrations of < or = 3.0 g/dl than in those with levels of > 3.0 g/dl (34.6 vs 23.5 ml min-1 m-2, P = 0.05). Total CL was directly related to %unbound (r2 = 0.61, P = 0.0004). Unbound CL was unrelated to either serum albumin or %unbound. These results demonstrate that hypoalbuminemia is independently associated with an increased etoposide %unbound and rapid total CL after the administration of high-dose etoposide. Unbound CL in hypoalbuminemic patients is unchanged in the presence of normal total bilirubin values.