Dose-exposure-response relationship between AZD6738 and peripheral monocytes.

e14063Background: AZD6738 is a potent, selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) serine/threonine-specific protein kinase with good selectivity against other phosphatidylinositol 3-kinase-related kinase (PIKK) family members. To support dose/schedule guidance through mathematical modelling of clinical pharmacokinetic/pharmacodynamic relationships, we sought to determine quantitative pharmacodynamic effects of AZD6738 in peripheral blood with respect to drug exposure. Methods: We assessed peripheral blood cell subpopulations in clinical studies of AZD6738 used either as a monotherapy, a combination with the PARP-1 inhibitor olaparib and in combination with the PD-L1 inhibitor durvalumab through both blood analyser and flow cytometry characterization. Peripheral pharmacokinetics of AZD6738 were also assessed. Results: Levels of peripheral monocytes were suppressed in a dose-dependent manner for the duration of AZD6738 dosing resulting in a decrease of up to 80% within the first...