Abstract
AZD7648 is a potent inhibitor of DNA-dependent protein kinase (DNA-PK), which is part of the non-homologous end-joining DNA repair pathway. When combined with the PARP inhibitor olaparib, AZD7648 shows robust combination activity in pre-clinical ATM-knockout mouse xenograft models. To understand the combination activity of AZD7648 and olaparib, we developed a semi-mechanistic pharmacokinetic/pharmacodynamic (PK-PD) model that incorporates the mechanism of action for each drug which links to proliferating, quiescent, and dying cell states with an additional Allee effect-like term to account for the non-linear growth and regression observed at low cell densities. Model parameters were fitted to training data sets that contained continuous treatment of either monotherapy or the combination. The observed interaction of AZD7648 on olaparib PK was incorporated in the PK-PD model by an effect function specific for each of the drug's MoA and was found essential to quantify drug effects at high dose levels of combination treatments. The model was able to adequately describe the observed efficacy for both monotherapy and sustained regressions in combination groups, mainly driven by maintaining a > 2:1 AUC ratio of apoptotic:proliferating cell fractions. We found that this model was suitable for forecasting intermittent dosing schedules a priori and resulted in accurate predictions when compared to xenograft efficacy data, without the need for extra, descriptive terms to describe supra-additive effects under combined dose regimes. This model provides quantitative understanding on the combination effect of AZD7648 and olaparib and allows for the exploration of the full exposure landscape without the need to experimentally test all scenarios. Furthermore, the model can be utilized to assess what exposures would be necessary in the clinic by linking it to observed or predicted human PK exposures. The model suggests 64.9 uM olaparib is sufficient to achieve tumor stasis in the absence of AZD7648, while the combination of AZD7648 and olaparib only requires plasma concentrations of 20.2 uM AZD7648 and 19.9 uM olaparib at steady-state to achieve the same effect.