Cancer Chemotherapy and Pharmacology

, Volume 76, Issue 2, pp 343–356 | Cite as

Validation of a predictive modeling approach to demonstrate the relative efficacy of three different schedules of the AKT inhibitor AZD5363

  • James W. T. Yates
  • Phillippa Dudley
  • Jane Cheng
  • Celina D’Cruz
  • Barry R. Davies
Original Article
  • 302 Downloads

Abstract

Purpose

Intermittent dosing of inhibitors of the PI3K/AKT/mTOR network offers the potential to maximize the therapeutic margin. Here, we validate a predictive modeling approach to establish the relative efficacy of continuous and two intermittent dosing schedules of the AKT inhibitor AZD5363.

Methods

A mathematical model of pharmacokinetics, pharmacodynamics and anti-tumor effect was constructed based upon experimental data from dosing regimens that give constant and transient inhibition of the AKT pathway.

Results

Continuous and intermittent dosing of AZD5363 inhibited growth of BT474c xenografts and caused dose- and time-dependent inhibition of AKT substrate phosphorylation. Both dosing schedules inhibited proliferation, but a higher intermittent dose also induced apoptosis. The mathematical model described this pharmacodynamic and efficacy data well, for both monotherapy and combination dosing with docetaxel, and predicted that equivalent efficacy could be achieved at 1.3- and 1.7× continuous dose when AZD5363 was dosed intermittently for 4 and 2 days per week, respectively. These predictions were confirmed in two independent xenograft models. Moreover, the model also correctly predicted the relative efficacy of three different sequences of intermittent dosing of AZD5363 with docetaxel.

Conclusions

Equivalent anti-tumor activity to continuous dosing can be achieved at modestly increased intermittent doses of AZD5363. These intermittent dosing regimens may potentially overcome tolerability issues seen with continuous dosing and enable greater flexibility of dosing schedule in combination with other agents, including chemotherapy.

Keywords

PKPD Combination therapy Kinase inhibitors Mathematical modeling 

Notes

Acknowledgments

AZD5363 was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

Conflict of interest

All authors are employees of AstraZeneca.

Supplementary material

280_2015_2795_MOESM1_ESM.docx (80 kb)
Supplementary material 1 (DOCX 80 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • James W. T. Yates
    • 1
  • Phillippa Dudley
    • 1
  • Jane Cheng
    • 2
  • Celina D’Cruz
    • 2
  • Barry R. Davies
    • 1
  1. 1.Oncology iMEDAstraZenecaMacclesfieldUK
  2. 2.Oncology iMEDAstraZenecaWalthamUSA

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