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

Melanie White-Koning, Elodie Civade, Birgit Geoerger, Fabienne Thomas, Marie Cécile Le Deley, Isabelle Hennebelle, Jean Pierre Delord, Etienne Chatelut, Gilles Vassal

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    35 Citations (Scopus)

    Résumé

    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.

    langue originaleAnglais
    Pages (de - à)4862-4871
    Nombre de pages10
    journalClinical Cancer Research
    Volume17
    Numéro de publication14
    Les DOIs
    étatPublié - 15 juil. 2011

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