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Cancer Chemotherapy and Pharmacology

, Volume 75, Issue 1, pp 111–121 | Cite as

Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies

  • Eleonora Marostica
  • Juthamas Sukbuntherng
  • David Loury
  • Jan de Jong
  • Xavier Woot de Trixhe
  • An Vermeulen
  • Giuseppe De Nicolao
  • Susan O’Brien
  • John C. Byrd
  • Ranjana Advani
  • Jesse McGreivy
  • Italo Poggesi
Original Article

Abstract

Purpose

Ibrutinib is an oral Bruton’s tyrosine kinase inhibitor, recently approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) patients with at least one prior therapy. We developed a population pharmacokinetic (PK) model for ibrutinib in patients.

Methods

Ibrutinib PK data (3,477 observations/245 patients) were available from the following clinical studies: (1) A phase I dose-escalation study in recurrent B cell malignancies (dose levels of 1.25–12.5 mg/kg/day and fixed dose of 560 mg/day); (2) a phase II study in MCL (fixed dose level of 560 mg/day); (3) a phase Ib/II dose-finding study in CLL (fixed dose levels of 420 and 840 mg/day). Different compartmental PK models were explored using nonlinear mixed effects modeling.

Results

A two-compartment PK model with sequential zero–first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively.

Conclusions

The proposed population PK model was able to describe the plasma concentration–time profiles of ibrutinib across various trials. The linear model indicated that the compound’s PK was dose independent and time independent.

Keywords

Phase I–II ADME Nonlinear mixed effects model Covariate analysis 

Notes

Acknowledgments

The authors thank Purvi Jejurkar (Pharmacyclics) for bioanalytical support and Rishabh Pandey (SIRO Clinpharm Pvt. Ltd.) for additional editorial assistance. The authors also thank the study participants, without whom this study would not have been accomplished. The authors received financial support from Janssen Research and Development and Pharmacyclics.

Conflict of interest

Juthamas Sukbuntherng, David Loury, and Jesse McGreivy are employees of Pharmacyclics; Jan de Jong, Xavier Woot de Trixhe, An Vermeulen, and Italo Poggesi are employees of Janssen R&D.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Eleonora Marostica
    • 1
  • Juthamas Sukbuntherng
    • 2
  • David Loury
    • 2
  • Jan de Jong
    • 3
  • Xavier Woot de Trixhe
    • 4
  • An Vermeulen
    • 4
  • Giuseppe De Nicolao
    • 1
  • Susan O’Brien
    • 5
  • John C. Byrd
    • 6
  • Ranjana Advani
    • 7
  • Jesse McGreivy
    • 2
  • Italo Poggesi
    • 4
    • 8
  1. 1.Department of Electrical, Computer and Biomedical EngineeringUniversity of PaviaPaviaItaly
  2. 2.PharmacyclicsSunnyvaleUSA
  3. 3.Janssen Research and DevelopmentLa JollaUSA
  4. 4.Janssen Research and DevelopmentBeerseBelgium
  5. 5.University of Texas M.D. Anderson Cancer CenterHoustonUSA
  6. 6.Ohio State UniversityColumbusUSA
  7. 7.Stanford Cancer InstituteStanfordUSA
  8. 8.Model Based Drug DevelopmentJanssen Research and Development, c/o Janssen Cilag S.p.A.Cologno M.seItaly

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