Abstract 1042: Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833

Abstract

Abstract AZD9833 is a potent, orally delivered, non-steroidal selective estrogen receptor degrader (SERD) that both antagonizes and degrades ERα. It is currently in clinical testing for the treatment of ER+ metastatic breast cancer (SERENA-1; NCT03616587). While ER is a clinically validated target, sustained inhibition of the target via oral delivery has proven an elusive goal. Despite intensive research, no oral SERD options are currently approved. Poor pharmacokinetic (PK) properties and/or short half-life (t ½) are often underlying features that limit oral SERD candidates from once or twice daily dose regimens. AZD9833 is a clinical stage next generation oral SERD that may overcome these challenges. The pre-clinical PK properties of AZD9833 are consistent with once daily oral dosing in patients and are reported herein. AZD9833 is a low molecular weight (<500 Da), low lipophilicity (logD <3) base with good permeability characteristics. High volume of distribution (6-13 L/kg) and high bioavailability were observed in preclinical species. The in vitro hepatic metabolic clearance (CLint) for AZD9833 varied across species and were found to be nonlinear as a function of concentration. This nonlinear behaviour most strongly manifested in dog where in vivo bioavailability was <2 or 95 %F depending on dose. To explain these observations, detailed in vitro mechanistic studies were conducted and physiologically based PK (PBPK) models were created. Cytochrome P450 phenotyping studies suggest dog clearance is mediated by CYP2D15 whereas CYP3A is the dominant P450 isoform responsible for clearance in human. In vitro CLint vs. concentration studies exhibited a low Km in dog (0.2 μM) relative to human (2 μM) and other species. To further our understanding, we constructed PBPK models which demonstrated that the dose dependent exposures in dog were predictable. The human model suggests that nonlinear behaviour will manifest well above predicted efficacious doses. Modeling also allowed us to assess the potential for drug-drug interactions with likely co-medications such as CDK 4/6 inhibitors. The PBPK predictions of good human exposure and long t ½ are being explored in the ongoing clinical trial. Citation Format: Eric T. Gangl, Roshini Markandu, Pradeep Sharma, Andy Sykes, Petar Pop-Damkov, Pablo Morentin Gutierrez, James S. Scott, Dermot F. McGinnity, Adrian J. Fretland, Teresa Klinowska. Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1042.