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

G.Würthwein1, T.Klingebiel2, S.Krümpelmann3, M.Metz4, K.Schwenker4, C.Lanvers1, J. Boos1

1 University Children´s Hospital Münster, Department of Pediatric Hematology and Oncology, 2 University Hospital Frankfurt, Department of Pediatric Hematology and Oncology, 3 Hospital for Children, Darmstadt, 4 University Children´s Hospital Tübingen

Objectives: Many conditioning regimens contain high dose (HD) etoposide (Eto). Linearity of pharmacokinetics for Eto from low dose (LD) to HD schedules was observed in adults, there was no difference between the kinetics in adults and children at lower doses. Data on the kinetics in children under HD conditions are, however, limited.

Methods: Based on clinical drug monitoring data, pharmacokinetics after high dose Eto (40 mg/kg i.v. once as 4 h infusion, 1 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 (BMT) after different conditioning regimens. Blood samples were collected until 97 h after the end of infusion. The population analysis (P-Pharm 1.5) 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.

Results: Data were best described by a three compartment model with t½ a of 0.28 h ± 3.2 %, t½ ß of 3.6 h ± 16.9 % and t½ g of 44.2 h ± 56.5 %, respectively (meangeom ± CVgeom). Clearance (CL) was 15.5 ml/min/m2 ± 30.6 % (meangeom ± CVgeom). The fraction of unbound Eto (fu) was 7.0 % (4.3 %  -  11.9 %) (median (range)), with high intra-individual variability. An increase in fu with increasing total Eto was observed.

Discussion: Most published data on the PK of Eto showed biexponential Eto disappearance. Besides the present drug monitoring there are only few studies reported in literature after high dose Eto that found a third compartment - all these studies showed long times of sample collection after end of infusion. Eto CL was low compared to data reported in the literature. The relatively low Eto CL together with findings of a deep third compartment may not only influence total AUC but also plasma drug concentration at time of BMT. The question of a principally lower Eto CL in children, as compared to adults, after high dose treatment remains open.

Ref.: Würthwein G. et al: Population pharmacokinetics of high-dose etoposide in children receiving different conditioning regimens. Anti-Cancer Drugs: 13: 101-110, 2002