AZD7648 is a potent and highly selective inhibitor of DNA-dependent protein kinase (DNA-PK) that has been nominated for clinical development. DNA-PK is a nuclear serine/threonine protein kinase complex involved in DNA damage repair, and a key component of the non-homologous end joining repair mechanism of double strand breaks (DSBs). This work aimed to explore the relationships between pharmacokinetics (PK), pharmacodynamics (PD) and xenograft tumor volume from pre-clinical studies, in order to define PD requirements for pre-clinical efficacy, and to estimate a target clinical dose for AZD7648 in combination with DSB-inducing agents such as olaparib or pegylated liposomal doxorubicin (PLD). A population-based modelling approach was used to explore the PK of AZD7648 in mice. The PK model was developed using data from full PK profiles (multiple longitudinal samples per mouse), and validated against terminal sample PK data. The potential influences of strain-dependence, time non-linearity, and interaction with olaparib on the pharmacokinetics of AZD7648 were investigated. Direct and indirect inhibition PD models were fitted to the responses of biomarkers describing target engagement (pDNA-PK) or proximal downstream effects (pRPA32 (S4/8) and γH2AX). A compartmental model accurately described AZD7648 PK in mice, with rapid absorption, dose-proportional PK across the range of doses tested, time-independent parameters and no effect of olaparib co-dosing on AZD7648 PK. The PD of proximal target engagement biomarkers were best described with an Imax model with very rapid turnover (<10 minutes), which showed there was negligible delay (due to tumor distribution or pharmacology) and effectively a direct relationship between systemic PK and xenograft biomarker inhibition. Across a number of FaDu ATM KO and BT474c xenograft tumor studies, the duration of cover over IC90 correlated with efficacy in combination with olaparib or PLD, demonstrating the importance of inhibiting DNA-PK for an extended duration in each dosing period. This result was applied to define a target level and duration of PD inhibition, and, when combined with predicted human PK behaviour, a target clinical dose for AZD7648 in combination with DSB-inducing agents to inform the clinical investigation of AZD7648.

Citation Format: Michael Davies, Joost de Jongh, Emma Dean, Jacquelline H. Fok, Frederick W. Goldberg, Neil James, Ankur Karmokar, Antonio Ramos-Montoya, Anna Staniszewska, Andy Sykes, Tamara van Steeg, Elaine Cadogan. Exploration of pre-clinical relationships between pharmacokinetics, pharmacodynamics and tumor volume for the novel DNA-PK inhibitor AZD7648 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3511.