Developmental pharmacokinetics of etoposide in 67 children: lack of dexamethasone effect.
OBJECTIVE
A randomized clinical trial examined whether dexamethasone administration prior to ondansetron followed by etoposide and carboplatin infusions, and single-nucleotide polymorphisms (SNPs) of CYP3A4, CYP3A5 and MDR1 genes could modify etoposide pharmacokinetics in pediatric patients.


METHODS
Patients, 67 children, aged 14 weeks to 16.7 years, were treated for various malignancies and received either 3- or 5-day courses of etoposide and carboplatin: these two drugs were always administered after ondansetron infusion but combined or not with dexamethasone 5 mg/m²/day 30 min prior to etoposide infusion. Population pharmacokinetics was modeled using a non-linear mixed effect model program (Monolix version 31 s).


RESULTS
Etoposide pharmacokinetics was ascribed to a 2-compartment model. The most significant covariate effect was bodyweight (BW), so the parameters were standardized to a 70-kg BW using the allometric ¾ or 1 power model for clearance (CL, Q) or volume terms (V), respectively. The population means for clearance and central volume of distribution were 2.05 l/h/70 kg and 9.21 l/70 kg with the corresponding between-subject variabilities, 0.26 and 0.28. Dexamethasone treatment had no effect on CL, either at the first or at the last administration occasion. CYP3A and MDR1 examined SNPs had no significant effect.


CONCLUSIONS
Pharmacokinetics of etoposide was influenced by BW on an allometric basis in this pediatric population. Dexamethasone did not influence etoposide pharmacokinetics during these 3-5 days courses. These results should allow a better individualization of etoposide dosing in children.
Urien
Saik
S
CIC-0901 Inserm Necker-Cochin and EA-3620, Paris, France. saik.urien@svp.aphp.fr
Doz
François
F
Giraud
Carole
C
Rey
Elisabeth
E
Gentet
Jean-Claude
JC
Chastagner
Pascal
P
Vassal
Gilles
G
Corradini
Nadège
N
Auvrignon
Anne
A
Leblond
Pierre
P
Rubie
Hervé
H
Treluyer
Jean-Marc
JM
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000932:Antiemetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight; D016190:Carboplatin / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017711:Nonlinear Dynamics; D017294:Ondansetron / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000932:Antiemetics; D017294:Ondansetron; D005047:Etoposide; D003907:Dexamethasone; D016190:Carboplatin; D051544:Cytochrome P-450 CYP3A