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Safety and CSF distribution of high-dose erlotinib and gefitinib in patients of non–small cell lung cancer (NSCLC) with brain metastases

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Patients of non–small cell lung cancer (NSCLC) with brain metastases have limited treatment options. High-dose erlotinib (HDE) and gefitinib (HDG) have been tried in the past. This study investigates the cerebrospinal fluid (CSF) disposition and safety of both, high-dose erlotinib and gefitinib regimens.

Methods

Eleven and nine patients were treated with erlotinib and gefitinib, respectively. All patients received 1 week of standard dose of erlotinib (150 mg OD) or gefitinib (250 mg OD), followed by the high dose (1500 mg weekly for erlotinib and 1250 mg OD for gefitinib) from day 8. Blood and CSF samples were collected on days 7 and 15, 4 h after the morning dose and drug levels determined using LC-MS/MS. Adverse events were documented as per CTCAE 4.03 till day 15.

Results

Pulsatile HDE and daily HDG resulted in 1.4- and 1.9-fold increase in CSF levels, respectively. A constant 2% CSF penetration rate was observed across both doses of erlotinib, while for gefitinib the penetration rate for high dose was half that of the standard dose suggesting a nonlinear disposition. Three patients on HDE treatment discontinued treatment after the first dose due to intolerable toxicities, whereas HDG was better tolerated with no treatment discontinuations. Since CSF disposition of gefitinib followed saturable kinetics, a lower dose of 750 mg was found to achieve CSF concentrations comparable to that of the 1250 mg dose.

Conclusions

HDG was better tolerated than HDE. CSF disposition of gefitinib was found to be saturable at a higher dose. Based on these findings, the dose of 750 mg OD should be considered for further evaluation in this setting.

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Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are thankful to Tata Memorial Centre for funding this study.

We thank the patients and their families for participating in this trial.

Funding

This work was supported by the Tata Memorial Centre intramural grant, Mumbai, India.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, 410210, India

    Bharati Shriyan, Deepali Patil, Murari Gurjar, Manjunath Nookala, Anand Patil & Vikram Gota

  2. Department of Biostatistics, ACTREC, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, 410210, India

    Sadhana Kannan

  3. Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, 400012, India

    Vijay Patil, Amit Joshi, Vanita Noronha & Kumar Prabhash

  4. Homi Bhabha National Institute, Mumbai, 400094, India

    Vijay Patil, Amit Joshi, Vanita Noronha, Kumar Prabhash & Vikram Gota

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  1. Bharati Shriyan
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Contributions

Dr. Vikram Gota and Dr. Kumar Prabhash were involved in conceiving and designing the study. Drs. Kumar Prabhash, Vijay Patil, Vanita Noronha and Amit Joshi provided medical care to the trial participants. Ms. Deepali Patil was involved in collecting the patient data. Mr. Murari Gurjar was responsible for analysing patient samples. Ms. Sadhana Kannan was involved in statistical analysis. Ms. Bharati Shriyan was involved in analysing the data, drafting the manuscript and preparing for the publication. Dr. Manjunath Nookala and Mr. Anand Patil were involved in fine tuning the manuscript. Dr. Vikram Gota was also involved in interpreting the data and reviewing the manuscript critically.

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Correspondence to Vikram Gota.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (TMC-ACTREC IEC-III, Registration number: ECR/149/Inst/MH/2013) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Shriyan, B., Patil, D., Gurjar, M. et al. Safety and CSF distribution of high-dose erlotinib and gefitinib in patients of non–small cell lung cancer (NSCLC) with brain metastases. Eur J Clin Pharmacol 76, 1427–1436 (2020). https://doi.org/10.1007/s00228-020-02926-9

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