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

Abstract

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.

• Authors: Melanie White-Koning, Elodie Civade, Birgit Geoerger, Fabienne Thomas, Marie-Cécile Le Deley, Isabelle Hennebelle, Jean-Pierre Delord, Etienne Chatelut, Gilles Vassal
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 14 Pg. 4862-71 (Jul 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21653689 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• OSI-420
• Protein Kinase Inhibitors
• Quinazolines
• Erlotinib Hydrochloride
• CYP3A5 protein, human
• Cytochrome P-450 CYP3A
• ErbB Receptors

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, blood, pharmacokinetics)
• Brain Neoplasms (blood, genetics)
• Carcinoma, Squamous Cell (blood, genetics)
• Child
• Child, Preschool
• Cytochrome P-450 CYP3A (genetics)
• ErbB Receptors (antagonists & inhibitors)
• Erlotinib Hydrochloride
• Exanthema (chemically induced)
• Female
• Head and Neck Neoplasms (blood, genetics)
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide (genetics)
• Protein Kinase Inhibitors (adverse effects, blood, pharmacokinetics)
• Quinazolines (adverse effects, blood, pharmacokinetics)
• Squamous Cell Carcinoma of Head and Neck
• Young Adult