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Ibrutinib brain distribution: a preclinical study

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Abstract

Purpose

Central nervous system (CNS) dissemination occurs in 4.1% of mantle cell lymphoma (MCL) patients and clinically significant CNS involvement in chronic lymphocytic leukemia (CLL) patients reaches 4%. Ibrutinib, an orally administered Bruton’s tyrosine kinase (BTK) inhibitor, has shown substantial activity in CLL or MCL patients with CNS localization, and in primary central nervous system lymphoma (PCNSL). The drug efficacy to treat primary or secondary CNS impairments relies on its brain distribution through the blood–brain barrier (BBB), the aim of the present work was to study the brain distribution of ibrutinib using an in vivo mice model.

Methods

Brain and plasma pharmacokinetics of ibrutinib were assessed in a healthy Swiss mice model. Brain accumulation of ibrutinib was evaluated through an escalation single-dose study and a multiple-dose study in whole brain and in its specific anatomic structures. Ibrutinib plasma and brain quantification was performed using a validated liquid-chromatography mass tandem spectrometry method.

Results

Maximal concentration of ibrutinib in plasma and brain were close thus showing that ibrutinib rapidly crosses the BBB in 0.29 h (0.2–0.32 h) [median (min–max)]. Ibrutinib brain exposure was also correlated to the dose, and correlated to plasma exposure. AUC0−t brain to AUC0−t plasma ratio average for ibrutinib was found to reach 0.7 and ibrutinib accumulates in the ventricle area.

Conclusion

The high level of ibrutinib brain distribution supports the clinical efficacy of this drug in CNS localization of MCL, CLL or PCNSL.

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Fig. 1

Abbreviations

AUC:

Area under the curve

MCL:

Mantle cell lymphoma

CNS:

Central nervous system

PCNSL:

Central nervous system lymphoma

IBR:

Ibrutinib

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Authors and Affiliations

  1. Pharmacology Department, Saint-Louis Hospital, AP-HP, 1 Avenue Claude Vellefaux, 75010, Paris, France

    Lauriane Goldwirt, Alain Ple, Hélène Sauvageon & Samia Mourah

  2. INSERM UMR_S976, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France

    Lauriane Goldwirt & Samia Mourah

  3. Department of Pediatric Neurosurgery, Necker Hospital, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, 75015, Paris, France

    Kevin Beccaria

Authors
  1. Lauriane Goldwirt
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  2. Kevin Beccaria
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  3. Alain Ple
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  4. Hélène Sauvageon
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Corresponding author

Correspondence to Lauriane Goldwirt.

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The authors have no conflict of interest to declare.

Ethical statement

All procedures involving animals were conducted in strict adherence to the French law for animal care and handling. (Authorization no. 2015071616316531.01).

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Goldwirt, L., Beccaria, K., Ple, A. et al. Ibrutinib brain distribution: a preclinical study. Cancer Chemother Pharmacol 81, 783–789 (2018). https://doi.org/10.1007/s00280-018-3546-3

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  • DOI: https://doi.org/10.1007/s00280-018-3546-3

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