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 ( 2677 G > T/A and 6986 G > 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. Clin Cancer Res; 17(14); 4862–71. ©2011 AACR .