Population pharmacokinetics of high-dose etoposide in children receiving different conditioning regimens.

Pharmacokinetics after high-dose (HD) etoposide (Eto) (40 mg/kg i.v. once as 4-h infusion, one patient 20 mg/kg i.v. as 4-h infusion, for 3 consecutive days) were studied in 31 children and young adults (age 0.8-23.7 years, median: 8.0 years) undergoing bone marrow transplantation after different conditioning regimens. Blood samples were collected until 97 h after the end of infusion. The population analysis of the first part of data (112 samples/21 patients, well documented) served to establish the pharmacokinetic model. The same data combined with the second part of data (50 samples/10 patients, 'intention to treat') then served to calculate the final population model. Data were best described by a three-compartment model with t1/2alpha = 0.28 h +/- 3.2%, t1/2beta = 3.6 h +/- 16.9% and t1/2gamma = 44.2 h +/- 56.5%, respectively (mean(geom) +/- CV(geom)). Clearance (CL) was 15.5 ml/min/m2 +/- 30.6% (mean(geom) +/- CV(geom)) and thus at the lower range of data reported in the literature. The fraction of unbound Eto (fu) was 7.0% (4.3-11.9%) [median (range)], with high intra-individual variability. An increase in f(u) with increasing total Eto was observed. The question of a principally lower Eto CL in children, as compared to adults, after HD treatment remains open.