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



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.


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.


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.


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.


PKPD Combination therapy Kinase inhibitors Mathematical modeling 



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)


  1. 1.
    Vasudevan KM, Garraway LA (2011) AKT signaling in physiology and disease. Curr Top Microbiol 347:105–133Google Scholar
  2. 2.
    Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka et al (2010) MK-2206, an allosteric AKT inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 9:1956–1967PubMedCrossRefGoogle Scholar
  3. 3.
    Davies BR, Greenwood H, Dudley P, Crafter C, Yu D, Zhang J et al (2012) Preclinical pharmacology of AZD5363, an orally bioavailable inhibitor of AKT: pharmacodynamics, antitumor activity and correlation of monotherapy activity with genetic background. Mol Cancer Ther 11:873–887PubMedCrossRefGoogle Scholar
  4. 4.
    Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K et al (2011) First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29:4688–4695PubMedCrossRefGoogle Scholar
  5. 5.
    Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J et al (2013) Targeting activated AKT with GDC-0068, a novel selective AKT inhibitor that is efficacious in multiple tumor models. Clin Cancer Res 19:1760–1772PubMedCrossRefGoogle Scholar
  6. 6.
    Davies AM, Ho C, Primo NL, Mack P, Gumerlock PH, Grandara DR (2006) Pharmacodynamic separation of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy in non-small-cell lung cancer. Clin Lung Cancer 7:385PubMedCrossRefGoogle Scholar
  7. 7.
    Martinelli G, Soverini S, Iacobucci I, Baccarini M (2009) Intermittent targeting as a tool to minimize toxicity of tyrosine kinase inhibitor therapy. Nat Clin Pract 6(2):68CrossRefGoogle Scholar
  8. 8.
    Shah NP, Kantarjian HM, Kim DW, Réa D, Dorlhiac-Llacer PE, Milone JH et al (2008) Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26:3204–3212PubMedCrossRefGoogle Scholar
  9. 9.
    Solit DB, She Y, Lobo J, Kris MG, Scher HI, Rosen N et al (2005) Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res 11:1983–1989PubMedCrossRefGoogle Scholar
  10. 10.
    Wang S, Zhou Q, Gallo JM (2009) Demonstration of the equivalent pharmacokinetic/pharmacodynamic dosing strategy in a multiple-dose study of gefitinib. Mol Cancer Ther 8(6):1438PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Wang X, Zhang L, Goldberg SN, Bhasin M, Brown V, Alsop DC et al (2011) High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma. J Transl Med 9:220PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Kraus M, Wang Y, Aleksandrowicz D, Bachman E, Szewczak A, Walker D et al (2012) Efficacious intermittent dosing of a novel JAK2 inhibitor in mouse models of polycythemia vera. PLoS ONE 7:e37707CrossRefGoogle Scholar
  13. 13.
    Fury MG, Solit DB, Su YB, Rosen N, Sirotnak FM, Smith RP et al (2007) A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 59:467–475PubMedCrossRefGoogle Scholar
  14. 14.
    Sangha R, Davies AM, Lara PN Jr, Mack PC, Beckett LA, Hesketh PJ et al (2011) Intercalated erlotinib-docetaxel dosing schedules designed to achieve pharmacodynamic separation: results of a phase I/II trial. J Thorac Oncol 6:2112–2119PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    La Rosée P, Martiat P, Leitner A, Klag T, Müller MC, Erben P et al (2013) Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib. Ann Hematol 92:1345–1350PubMedCrossRefGoogle Scholar
  16. 16.
    Simeoni M, Magni P, Cammia C, De Nicolao G, Croci V, Pesenti E, Germani M, Poggesi I, Rochetti M (2004) Predictive pharmacokinetic-pharmacodynamic modelling of tumour growth kinetics in xenograft models after administration of anticancer agents. Cancer Res 64:1094–1101PubMedCrossRefGoogle Scholar
  17. 17.
    Ribba B, Watkin E, Tod M, Girard P, Grenier E, You B, Giraudo E, Freyer G (2011) A model of vascular tumour growth in mice combining longitudinal tumour size data with histological biomarkers. Eur J Cancer 47:479–490PubMedCrossRefGoogle Scholar
  18. 18.
    Evans N, Dimelow R, Yates J (2013) Modeling of tumour growth and cytotoxic effect of docetaxel in xenografts. Comput Methods Programs Biomed 114:e3–e13PubMedCrossRefGoogle Scholar
  19. 19.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Annovazzi L, Mellai M, Caldera V, Valente G, Tessitore L, Schiffer D (2009) mTOR, S6 and AKT expression in relation to proliferation and apoptosis/autophagy in glioma. Anticancer Res 29:3087–3094PubMedGoogle Scholar
  21. 21.
    Madhunapantula SV, Sharma A, Robertson GP (2007) PRAS40 deregulates apoptosis in melanoma. Cancer Res 67:3626–3636PubMedCrossRefGoogle Scholar
  22. 22.
    Ribba B, Holford NH, Magni P, Trocóniz I, Gueorguieva I, Girard P, Sarr C, Elishmereni M, Kloft C, Friberg LE (2014) A review of mixed-effects models of tumor growth and effects of anticancer drug treatment used in population analysis. CPT Pharmacomet Syst Pharmacol 3:e113CrossRefGoogle Scholar
  23. 23.
    Manning B (2004) Balancing AKT with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 167(3):399–403PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Banerji U, Ranson M, Schellens J, Esaki T, Dean E, Zivi A, Van der Noll R, Stockman P, Marotti M, Garrett M, Davies BR, Elvin P, Hastie A, Lawrence P, Cheung SY, Stephens C, Tamura K (2013) Results of two Phase 1 multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors. Abstract LB-66 AACR 2013 Google Scholar

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

Personalised recommendations