Validation of a predictive modeling approach to demonstrate the relative efficacy of three different schedules of the AKT inhibitor AZD5363
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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.
KeywordsPKPD 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.
- 1.Vasudevan KM, Garraway LA (2011) AKT signaling in physiology and disease. Curr Top Microbiol 347:105–133Google Scholar
- 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
- 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
- 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