Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 6, pp 1255–1264

Preclinical pharmacokinetic/pharmacodynamic/efficacy relationships for alisertib, an investigational small-molecule inhibitor of Aurora A kinase

  • Santhosh Palani
  • Mayankbhai Patel
  • Jessica Huck
  • Mengkun Zhang
  • Suresh K. Balani
  • Johnny Yang
  • Susan Chen
  • Jerome Mettetal
  • Mark Manfredi
  • Wen Chyi Shyu
  • Jeffrey A. Ecsedy
  • Arijit Chakravarty
Original Article

DOI: 10.1007/s00280-013-2305-8

Cite this article as:
Palani, S., Patel, M., Huck, J. et al. Cancer Chemother Pharmacol (2013) 72: 1255. doi:10.1007/s00280-013-2305-8

Abstract

Purpose

Alisertib (MLN8237) is an investigational inhibitor of Aurora A kinase (AAK). Aurora A plays an essential role in the regulation of spindle assembly and chromosome alignment during mitosis. Inhibition of Aurora A by alisertib in tissue culture has previously been demonstrated to lead to improper chromosomal alignment and disruption of spindle organization, resulting in a transient mitotic delay. The spindle organization defects induced by alisertib have been used to develop a pharmacodynamic (PD) assay for Aurora A inhibition based on the percentage of mitotic cells with proper chromosomal alignment at the metaphase plate (% aligned spindles, abbreviated as AS). The transient mitotic delay that occurs with AAK inhibition permits the use of the mitotic index (the fraction of cells in the population currently undergoing mitosis, abbreviated as MI) as an additional PD assay. When the two PD assays were used in Phase I clinical trials, the reduction in AS was strongly correlated with dose levels and exposures in patients from single time point PD measurements; however, MI failed to show any correlation. To further understand this clinical finding, we constructed PK/PD/efficacy models for AS and MI that can precisely capture the temporal dynamics of the PD markers from in vivo xenograft studies.

Methods

A PK/PD study was conducted using a single oral dose of alisertib at 3, 10, and 20 mg/kg in HCT-116 xenografts implanted subcutaneously in mice. An extravascular, two-compartmental pharmacokinetic (PK) model was used to describe the drug kinetics. Consistent with the mechanistic hypothesis for AAK inhibition, the PD biomarkers such as AS and MI were fitted to PK using a direct response inhibitory sigmoid model and an indirect response turnover model, respectively. The antitumor activity of alisertib dosed orally for 21 days with different dose levels and schedules was evaluated.

Results

The PK/PD models showed a fast, sustained response for AS after alisertib administration, whereas MI exhibited a slow, transient response. The PK/efficacy relationship for alisertib in HCT-116 xenografts closely corresponds to the PK/PD relationship for the PD markers, with all three IC50s in close agreement (303, 270, and 280 nM, respectively).

Conclusion

The PK/PD and PK/efficacy models show that both AS and MI are equally relevant as mechanism-based PD markers to capture drug activity. However, of the two PD markers, the fast, sustained response of AS makes it the only clinically viable PD marker for defining a dose–response relationship, as its maximal effect can be captured from a wider time window with a single PD sampling; while the window to capture dose-related MI response is narrower.

Keywords

Alisertib MLN8237 MLN8054 Aurora A kinase PK/PD modeling PD biomarkers 

Supplementary material

280_2013_2305_MOESM1_ESM.doc (3.3 mb)
Supplementary material 1 (DOC 3361 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Santhosh Palani
    • 1
  • Mayankbhai Patel
    • 1
  • Jessica Huck
    • 2
  • Mengkun Zhang
    • 2
  • Suresh K. Balani
    • 1
  • Johnny Yang
    • 1
  • Susan Chen
    • 1
  • Jerome Mettetal
    • 1
  • Mark Manfredi
    • 2
  • Wen Chyi Shyu
    • 1
  • Jeffrey A. Ecsedy
    • 3
  • Arijit Chakravarty
    • 1
    • 3
  1. 1.Drug Metabolism and PharmacokineticsMillennium: The Takeda Oncology CompanyCambridgeUSA
  2. 2.Department of Cancer PharmacologyMillennium: The Takeda Oncology CompanyCambridgeUSA
  3. 3.Translational MedicineMillennium: The Takeda Oncology CompanyCambridgeUSA