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Population Pharmacokinetics of Ibrutinib in Healthy Adults

European Journal of Drug Metabolism and Pharmacokinetics volume 46, pages 405–413 (2021)Cite this article

Abstract

Background and Objectives

Ibrutinib is an antineoplastic agent that reduces B-cell proliferation by inhibiting Bruton's tyrosine kinase. We describes population pharmacokinetics of ibrutinib in healthy adults, and explores potential patient characteristics associated with ibrutinib pharmacokinetics.

Methods

A population pharmacokinetic modeling approach was applied to 39 healthy subjects. Modeling was performed using Monolix (v.2019R2). Serial blood samples to measure the plasma ibrutinib concentration were collected following the oral administration of 140 mg ibrutinib on two different occasions under fasting conditions. Demographic and clinical information were evaluated as possible predictors of ibrutinib pharmacokinetics during model development. Simulations (using mlxR: R package v.4.0.2) following the administration of therapeutic doses were performed to explore the clinical implications of identified covariates on ibrutinib steady-state concentrations.

Results

A two-compartment model with zero order absorption best fit the data. Inter-individual and inter-occasion variability were quantified by the proposed model. We identified smoking status as a significant covariate associated with ibrutinib clearance. Smoking was found to increase ibrutinib clearance by approximately 60%, which resulted in a reduction in simulated steady-state concentrations by around 40%.

Conclusion

The model can be used to simulate clinical trials or various dosing scenarios. The proposed model can be used to optimize ibrutinib dosing based on the smoking status.

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Acknowledgements

This work has been carried out during sabbatical leave granted to the corresponding author (Mutasim Al-Ghazawi) from the University of Jordan during the academic year 2019-2020.

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Affiliations

  1. Department of Biopharmaceutics and Clinical Pharmacy, The University of Jordan, Amman, 11942, Jordan

    Mutasim Al-Ghazawi & Mohammad I. Saleh

  2. International Pharmaceutical Research Center, Amman, 11196, Jordan

    Omaima Najib, Isam Salem & Naji Najib

Authors
  1. Mutasim Al-Ghazawi
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  2. Mohammad I. Saleh
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  3. Omaima Najib
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  4. Isam Salem
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  5. Naji Najib
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Corresponding author

Correspondence to Mutasim Al-Ghazawi.

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Authors’ Contribution

MA and MS wrote the manuscript and analyzed the data. ON and NN designed the study and supervised the conduction of the study. IS designed the study and supervised bioanalysis of the study samples. All authors contributed towards the critical revision and approval of the manuscript.

Funding

Sabbatical leave granted by University of Jordan to Mutasim Al-Ghazawi.

Data Availability

Data are available on request from the corresponding author.

Conflict of Interest

Mutasim Al-Ghazawi, Mohammad I. Saleh, Omaima Najib, Isam Salem, Naji Najib have no conflict of interest to declare.

Ethics Approval

The study protocol was approved by the institutional review board of the International Pharmaceutical Research Center and the clinical trials Committee at the Jordan Food and Drug Administration.

Consent to Participate

Participants included in the study gave written informed consent before entering the study.

Consent to Publish

Not applicable.

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Al-Ghazawi, M., Saleh, M.I., Najib, O. et al. Population Pharmacokinetics of Ibrutinib in Healthy Adults. Eur J Drug Metab Pharmacokinet 46, 405–413 (2021). https://doi.org/10.1007/s13318-021-00679-z

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  • DOI: https://doi.org/10.1007/s13318-021-00679-z