Abstract 3019: Non-linear absorption pharmacokinetics (PK) of the ATR inhibitor AZD6738 in mice

Abstract

Abstract Introduction: AZD6738 is an inhibitor of the apical kinase Ataxia telangiectasia and Rad-3 related (ATR) and can block induction of DNA damage response signaling cascades that are initiated by ATR following chemotherapy or radiation cancer treatment. AZD6738 is in clinical development and also being used preclinically to mechanistically probe ATR signaling. Currently, little is known about AZD6738 PK, including bioavailability, and tissue distribution, and this information is valuable in both clinical and preclinical settings. Here we describe the intravenous (IV) and oral (PO) PK of AZD6738 in mice. Methods: Single doses of AZD6738 (IV 10 mg/kg, PO 2.0, 7.5, 20, or 75 mg/kg) were administered to female Balb/c mice. Mice were euthanized from 5 min to 24 h after dosing and plasma and tissues were collected and analyzed by an LC-MS/MS assay modified to include a sulfoxide and sulfone metabolite semiquantitatively. PK parameters and PO bioavailability were determined non-compartmentally (NCA) and compartmentally (CA). Dose linearity was assessed using naively pooled data and statistical comparison of dose normalized Cmax and AUC. ADAPT5 software was used to develop a CA model. Extraction ratio (EH) was calculated from IV administered mice to discern the contribution of hepatic first-pass metabolism to observed bioavailability. Results: IV data was best described by a two-compartment linear model. Negligible differences were observed between PO half-life at any dose (95.3 to 116 min) compared to the IV half-life (104 min). Increases in PO dose resulted in greater than proportional increases in exposure with statistical differences observed for dose-normalized Cmax and AUC. Concordantly, the bioavailability increased as dose increased, ranging from an F of 31.3% at 2.0 mg/kg to 81.3% at 75 mg/kg. A decrease in Tmax was also observed as dose increased, with a Tmax of 60 min at 2.0 mg/kg and 15 min at all other PO doses. As PO dose increased, decreases in sulfoxide dose-normalized AUC metabolic ratios were observed. A two-compartment model with an absorption compartment containing a saturable component capturing both efflux and first-pass metabolism was developed that adequately described the data with non-linear bioavailability. An empirical Emax fit to bioavailability as a function of dose determined the maximum bioavailability (Emax) to be 87.6% (95%CI 66.7-114%) and Km to be 3.99 (95% CI 1.06-11.3). Comparison of the EH of IV administered mice to the observed 2 mg/kg bioavailability determined ~50% passes the gut wall. Conclusion:AZD6738 was observed to display saturable intestinal efflux/first-pass metabolism resulting in dose-dependent bioavailability. Increased PO doses yield greater than proportional increases in exposure in mice. Presence of non-linear absorption PK in humans is conjecture. Funding: TL1TR001858, R50CA211241, P30CA047904 and American Foundation for Pharmaceutical Education, PA DoH Tobacco grant. Citation Format: Brian F. Kiesel, Jianxia Guo, Christopher J. Bakkenist, Jan H. Beumer. Non-linear absorption pharmacokinetics (PK) of the ATR inhibitor AZD6738 in mice [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 3019.