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Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 3, pp 593–602 | Cite as

Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia

  • Aksana KaeferEmail author
  • Jianning Yang
  • Peter Noertersheuser
  • Sven Mensing
  • Rod Humerickhouse
  • Walid Awni
  • Hao Xiong
Original Article

Abstract

Objective

Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of navitoclax as well as the time course of the platelet counts in cancer patients receiving navitoclax.

Methods

Data from 256 patients who received oral navitoclax (dose range 10–475 mg) as a 14/21-day schedule or a continuous once daily (QD) schedule were used to construct the model using NONMEM. The PK model was a two-compartmental model with a lag-time and a transit compartment in absorption. The PD model was a semi-physiological model that comprised a progenitor cell compartment, three transition compartments representing the maturation chain in the bone marrow and a peripheral blood compartment. Compared with the previously published models, the model established in this analysis applied a different feedback mechanism and introduced a new concept of progenitor cell “pool”, which describes a large pool of platelet progenitor cells at the beginning of navitoclax treatment.

Results

The PD model was able to describe a slight downward trend of platelet counts over the long-term navitoclax treatment as observed in around 8 % of the patients and the initial drop in platelets seen in our Phase 1/2a studies.

Conclusions

We have developed a new semi-physiological platelet model for describing fast drop of platelets after initial navitoclax administration and long-term decline of platelets after continuous administration of navitoclax.

Keywords

Navitoclax ABT-263 Pharmacokinetic Pharmacodynamic model Thrombocytopenia Platelet 

Notes

Conflict of interest

This study was sponsored by AbbVie Inc. AbbVie Inc. contributed to the study design; research; data interpretation; and writing, review and approval of the manuscript for publication. Aksana Kaefer, Jianning Yang, Peter Noertersheuser, Sven Mensing, Rod Humerickhouse, Walid Awni, Hao Xiong are employees of AbbVie Inc.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Aksana Kaefer
    • 1
    Email author
  • Jianning Yang
    • 1
  • Peter Noertersheuser
    • 2
  • Sven Mensing
    • 2
  • Rod Humerickhouse
    • 3
  • Walid Awni
    • 1
  • Hao Xiong
    • 1
  1. 1.Department of Clinical Pharmacology and PharmacometricsAbbVie Inc.North ChicagoUSA
  2. 2.PharmacometricsAbbVie Deutschland GmbH&Co.KGLudwigshafenGermany
  3. 3.OncologyAbbVie Inc.North ChicagoUSA

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