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01-10-2019 | Pharmacokinetics | Original Article

Pharmacokinetics and safety of erlotinib and its metabolite OSI-420 in infants and children with primary brain tumors

Authors: Samuel J. Reddick, Olivia Campagne, Jie Huang, Arzu Onar-Thomas, Alberto Broniscer, Amar Gajjar, Clinton F. Stewart

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2019

Abstract

Purpose

Erlotinib (Tarceva^®), a potent small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been evaluated to treat infants and children with primary brain tumors. The pharmacokinetics of erlotinib and its primary metabolite OSI-420 were characterized and exposure–safety associations were investigated.

Methods

This analysis involved patients enrolled in two clinical studies and receiving oral erlotinib once daily as part of treatment. Single-dose and steady-state erlotinib and OSI-420 plasma concentrations were assayed using HPLC–MS/MS methods. Population pharmacokinetic modeling and univariate covariate analysis evaluating demographic, clinical and selected CYP3A5, CYP3A4, ABCB1, and ABCG2 genotypes were performed. Associations between erlotinib and OSI-420 pharmacokinetics, and with toxicities (diarrhea and skin rash) occurring post-dose were explored.

Results

Data from 47 patients (0.7–19 years old) were collected and best fitted by one-compartment linear models. Erlotinib and OSI-420 apparent clearances (CL/F and CL_m/F_m) were higher in patients < 5 years compared to older patients (mean CL/F: 6.8 vs 3.6 L/h/m², and mean CL_m/F_m: 79 vs 38 L/h/m², p < 0.001), and were 1.62-fold and 1.73-fold higher in males compared to females (p < 0.01). Moreover, CL/F was 1.53-fold higher in wild-type patients than in patients heterozygous or homozygous mutant for ABCG2 rs55930652 (p < 0.05). Most of the toxicities reported were grade 1. No associations were found between drug pharmacokinetics and drug-induced toxicities.

Conclusions

Erlotinib therapy was well tolerated by pediatric patients with primary brain tumors. No dosing adjustments based on age or patient characteristics are recommended for this patient population.

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Title: Pharmacokinetics and safety of erlotinib and its metabolite OSI-420 in infants and children with primary brain tumors
Authors: Samuel J. Reddick
Olivia Campagne
Jie Huang
Arzu Onar-Thomas
Alberto Broniscer
Amar Gajjar
Clinton F. Stewart
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Keywords: Pharmacokinetics
Brain Tumor
Diarrhea
Diarrhea
Pediatrics
Erlotinib
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03921-3

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