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Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies

Clinical Pharmacokinetics volume 59, pages 1171–1183 (2020)Cite this article

Abstract

Background and Objective

Ibrutinib is used for the treatment of chronic lymphocytic leukemia and other lymphoid malignancies. The aim of this work is to develop a population pharmacokinetic model for ibrutinib and its dihydrodiol metabolite to quantify pharmacokinetic inter- and intra-individual variability, to evaluate the impact of several covariates on ibrutinib pharmacokinetic parameters, and to examine the relationship between exposure and clinical outcome.

Methods

Patients treated with ibrutinib were included in the study and followed up for 2 years. Pharmacokinetic blood samples were taken from months 1 to 12 after inclusion. Ibrutinib and dihydrodiol-ibrutinib concentrations were assessed using ultra-performance liquid chromatography tandem mass spectrometry. A population pharmacokinetic model was developed using NONMEM version 7.4.

Results

A total of 89 patients and 1501 plasma concentrations were included in the pharmacokinetic analysis. The best model consisted in two compartments for each molecule. Absorption was described by a sequential zero first-order process and a lag time. Ibrutinib was either metabolised into dihydrodiol-ibrutinib or excreted through other elimination routes. A link between the dosing compartment and the dihydrodiol-ibrutinib central compartment was added to assess for high first-pass hepatic metabolism. Ibrutinib clearance had 67% and 47% inter- and intra-individual variability, respectively, while dihydrodiol-ibrutinib clearance had 51% and 26% inter- and intra-individual variability, respectively. Observed ibrutinib exposure is significantly higher in patients carrying one copy of the cytochrome P450 3A4*22 variant (1167 ng.h/mL vs 743 ng.h/mL, respectively, p = 0.024). However, no covariates with a clinically relevant effect on ibrutinib or dihydrodiol-ibrutinib exposure were identified in the PK model. An external evaluation of the model was performed. Clinical outcome was expressed as the continuation or discontinuation of ibrutinib therapy 1 year after treatment initiation. Patients who had treatment discontinuation because of toxicity had significantly higher ibrutinib area under the curve (p = 0.047). No association was found between cessation of therapy due to disease progression and ibrutinib area under the curve in patients with chronic lymphocytic leukemia. For the seven patients with mantle cell lymphoma studied, an association trend was observed between disease progression and low exposure to ibrutinib.

Conclusions

We present the first population pharmacokinetic model describing ibrutinib and dihydrodiol-ibrutinib concentrations simultaneously. Large inter-individual variability and substantial intra-individual variability were estimated and could not be explained by any covariate. Higher plasma exposure to ibrutinib is associated with cessation of therapy due to the occurrence of adverse events within the first year of treatment. The association between disease progression and ibrutinib exposure in patients with mantle cell lymphoma should be further investigated.

Trial Registration

ClinicalTrials.gov no. NCT02824159.

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Affiliations

  1. Cancer Research Center of Toulouse, INSERM, UMR-1037, CNRS ERL5294, Paul Sabatier University, Toulouse, France

    Fanny Gallais, Loïc Ysebaert, Anne Quillet-Mary, Fabienne Thomas, Ben Allal, Etienne Chatelut & Mélanie White-Koning

  2. Department of Hematology, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse, France

    Loïc Ysebaert, Caroline Protin & Lucie Obéric

  3. Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance, Pharmacoepidemiology and Drug Information, INSERM, UMR-1027, Pharmacoepidemiology, Assessment of Drug Utilization and Drug Safety, CIC 1426, Toulouse University Hospital, Toulouse, France

    Fabien Despas

  4. Department of Medical and Clinical Pharmacology, Toulouse University Hospital, Toulouse, France

    Sandra De Barros

  5. Center for Pathophysiology of Toulouse Purpan, INSERM UMR1043, CNRS UMR5282, Paul Sabatier University, Toulouse, France

    Loïc Dupré

  6. Laboratory of Pharmacology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France

    Fabienne Thomas, Ben Allal & Etienne Chatelut

Authors
  1. Fanny Gallais
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  2. Loïc Ysebaert
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  3. Fabien Despas
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  4. Sandra De Barros
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  5. Loïc Dupré
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  6. Anne Quillet-Mary
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  7. Caroline Protin
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  8. Fabienne Thomas
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  9. Lucie Obéric
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  10. Ben Allal
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  11. Etienne Chatelut
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  12. Mélanie White-Koning
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Corresponding author

Correspondence to Loïc Ysebaert.

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Funding

This study has been supported by the French National Drug Agency (ANSM), the French National Research Agency (ANR, project CAPTOR PHUC-001), and the AVIESAN, INCa and INSERM Plan Cancer program (project C15092BS).

Conflict of interest

Loïc Ysebaert received grant support and honorarium fees from Roche, Abbvie, Gilead and Janssen, but not in the scope of the present study. Lucie Obéric received honorarium fees from Roche and Janssen, but not in the scope of the present study. Fanny Gallais, Fabien Despas, Sandra De Barros, Loïc Dupré, Anne Quillet-Mary, Caroline Protin, Fabienne Thomas, Ben Allal, Etienne Chatelut and Mélanie White-Koning have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

The study was conducted in compliance with ethical standards.

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All patients gave their written informed consent.

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Gallais, F., Ysebaert, L., Despas, F. et al. Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies. Clin Pharmacokinet 59, 1171–1183 (2020). https://doi.org/10.1007/s40262-020-00884-0

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  • DOI: https://doi.org/10.1007/s40262-020-00884-0