title: Population analysis of erlotinib in adults and children reveals pharmacokinetic characteristics as the main factor explaining tolerance particularities in children.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: EA4553, Institut Claudius Regaud et Université de Toulouse, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: White-Koning
authors.forename: Elodie
authors.initials: E
authors.lastname: Civade
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.forename: Fabienne
authors.initials: F
authors.lastname: Thomas
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Le Deley
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hennebelle
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000097:blood / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006258:Head and Neck Neoplasms / Q000097:blood / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000077195:Squamous Cell Carcinoma of Head and Neck; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C487471:OSI-420; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D066246:ErbB Receptors