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

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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 CLm/Fm) were higher in patients < 5 years compared to older patients (mean CL/F: 6.8 vs 3.6 L/h/m2, and mean CLm/Fm: 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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Change history

  • 07 January 2020

    In the original publication of the article, the authors wish to note an error in the section “Funding”.

  • 07 January 2020

    In the original publication of the article, the authors wish to note an error in the section ���Funding���.

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Acknowledgments

We thank the clinical PK nurses and nursing team at St. Jude Children’s Research Hospital for assistance in obtaining plasma samples; the Stewart laboratory for processing the samples; and the Hartwell Center for performing Illumina Chip. We also thank Drs. Carl Panetta, Paula Schaiquevich, and Mike Tagen for their contributions in the population pharmacokinetic analysis.

Funding

This work was supported by grants from the National Cancer Institute (R01CA154619, R25CA23944), the Cancer Center Support (CORE; CA21765), and the American Lebanese Syrian Associated Charities (ALSAC) at St. Jude Children’s Research Hospital.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA

    Samuel J. Reddick, Olivia Campagne & Clinton F. Stewart

  2. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Jie Huang & Arzu Onar-Thomas

  3. Division of Neuro-Oncology, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Alberto Broniscer & Amar Gajjar

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  1. Samuel J. Reddick
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Correspondence to Clinton F. Stewart.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the St. Jude Children’s Research Hospital Institutional Review Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Reddick, S.J., Campagne, O., Huang, J. et al. Pharmacokinetics and safety of erlotinib and its metabolite OSI-420 in infants and children with primary brain tumors. Cancer Chemother Pharmacol 84, 829–838 (2019). https://doi.org/10.1007/s00280-019-03921-3

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