Steady-state levels and bone marrow toxicity of etoposide in children and infants: does etoposide require age-dependent dose calculation?
OBJECTIVE
Most pediatric treatment protocols specify dose calculations for cytostatic drugs based on body-surface area (BSA). However, for children less than 1 year of age, calculation guidelines vary. Normally, reduced dosages are recommended with calculations based on body weight (BW). However, the optimal dose for infants should take age-dependent and drug-specific pharmacokinetic parameters into account.


METHODS
The current investigation focused on the effects of different dose-reduction rules on the steady-state levels (Css) of etoposide and related bone marrow toxicity. One hundred seventy three treatment courses in 78 children on a 96-hour continuous infusion schedule were monitored for Css (determined by high-performance liquid chromatography [HPLC]), and 100 courses were documented in detail with regard to dose calculation (125 mg/m2, 4.17/kg, or 2/3 x 4.17/kg) and toxicity.


RESULTS
Dose calculation on the basis of BSA led to Css of 4.9 +/- 1.2 micrograms/mL, which on the basis of BW was 3.5 +/- 1.1 micrograms/mL and 1.95 +/- 0.6 micrograms/mL (2/3.kg-dose), respectively. However, conversion of the latter levels to those expected with the regular square-meter-dose, resulted in values of 4.7 +/- 1.4 micrograms/mL and 4.2 +/- 1.2 micrograms/mL (/125 mg/m2). Lower etoposide Css levels resulted in less pronounced thrombocyte and WBC nadirs in the respective groups. The dose-calculation rules for infants, therefore, decreased both dose-intensity and related toxicity. Etoposide clearance rates related to BW (0.8 +/- 0.3 mL/min/kg) or BW (19 +/- 6 mL/min/m2) did not show any differences between children and infants, even in the age range of 3 to 12 months.


CONCLUSIONS
In the case of etoposide, special dose-calculation guidelines for infants are not substantiated by age-dependent pharmacokinetics or tolerance.
Department of Pediatric Hematology and Onkology, University of Münster, Germany.
J
J
Boos
S
S
Krümpelmann
P
P
Schulze-Westhoff
T
T
Euting
F
F
Berthold
H
H
Jürgens
D000293:Adolescent; D000375:Aging / Q000378:metabolism*; D001830:Body Surface Area; D001835:Body Weight; D001855:Bone Marrow Diseases / Q000139:chemically induced; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D007206:Individuality; D007223:Infant; D007262:Infusions, Intravenous; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism*
D005047:Etoposide