Defining preclinical efficacy with the DNAPK inhibitor AZD7648 in combination with olaparib: a minimal systems pharmacokinetic-pharmacodynamic model.

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. T

SUBMITTER: DeJongh J 

PROVIDER: S-EPMC11832700 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature