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 autolog ous bone marrow transplantation for advanced lymphoma after receiving high-dose etoposide (35-60 mg/kg) as a single intravenous infusion. Pr etreatment 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 con centrations and protein binding (%unbound) were determined by high-per formance liquid chromatography (HPLC) and equilibrium dialysis, respec tively. Pharmacokinetic parameters for unbound and total etoposide wer e calculated by nonlinear regression analysis using a two-compartment model. The mean (+/-SD) parameters for total etoposide included: clear ance (CL), 31.8 +/- 17.7 ml min-1 M-2; volume of distribution (V(ss)), 11.5 +/- 5.91/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 alb umin (r2 = 0.45, P = 0.0043). The mean %unbound at the end of the etop oside infusion was higher than that at the lowest measured concentrati on (21% vs 13%, respectively; P = 0.017), suggesting that concentratio n-dependent binding may occur after high etoposide doses. The median t otal CL was higher in patients with serum albumin concentrations of le ss-than-or-equal-to 3.0 g/dl than in those with levels of >3.0 g/dl (3 4.6 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 s erum albumin or %unbound. These results demonstrate that hypoalbuminem ia is independently associated with an increased etoposide %unbound an d rapid total CL after the administration of high-dose etoposide. Unbo und CL in hypoalbuminemic patients is unchanged in the presence of nor mal total bilirubin values.