Population analysis of erlotinib in adults and children reveals pharmacokinetic characteristics as the main factor explaining tolerance particularities in children.

PURPOSE

The aim of this pharmacokinetic-pharmacodynamic (PK-PD) analysis was to evaluate the pharmacologic characteristics of erlotinib and its main metabolite (OSI-420) in pediatric patients compared with those in adult patients.

EXPERIMENTAL DESIGN

Plasma concentrations of erlotinib and OSI-420 of 46 children with malignant brain tumors included in a phase I study and 42 adults with head and neck carcinoma were analyzed by a population-pharmacokinetic method (NONMEM). The effect of several covariates and single nucleotide polymorphisms (SNP) in ABCB1, ABCG2, and CYP3A5 on pharmacokinetic parameters was evaluated. PK/PD relationships between plasma drug exposure Area Under the Curve (AUC) at day 1 and skin toxicity were studied in children and compared with the relationship observed in adults.

RESULTS

A significant difference in erlotinib clearance (P = 0.0001), when expressed in L·h(-1)·kg(-1), was observed between children and adults with mean values of 0.146 and 0.095, respectively (mean difference = 0.051 L·h(-1)·kg(-1), SD = 0.0594). However, a common covariate model was obtained describing erlotinib clearance according to body weight, alanine aminotransferase, ABCB1, and CYP3A5 polymorphisms (2677G > T/A and 6986G > A) for both children and adult patients. The PK-PD relationship was very consistent between the children and adult groups with risk of skin toxicity rising with increasing erlotinib AUC.

CONCLUSIONS

The nonlinear population approach applied to pharmacokinetic data combined with a pharmacokinetic-pharmacodynamic analysis revealed that the higher recommended dose in children (125 mg/m(2)/day) compared with adults (90 mg/m(2)/day) is mainly due to pharmacokinetic rather than pharmacodynamic particularities.