Allosteric oncogenic mutations occur outside the canonical ATP-binding site of EGFR and HER2, for which there are no approved single agent therapies that target this family. BDTX-189 is a potent, selective, irreversible inhibitor of the family of nearly 50 allosteric EGFR and HER2 mutant variants. The goal of this translational analysis was to predict the clinical pharmacokinetic (PK) profile of BDTX-189 utilizing in vitro data on the absorption, distribution and metabolism of BDTX-189 as well as in vivo PK data in preclinical species. The prospective PK modeling was conducted prior to initiation of a Phase 1/2 study, to provide predictions of clinical exposures and active dose range. A challenge in the design of irreversible inhibitors with optimal PK properties is the lack of reliable methods to predict their disposition and elimination in human. The PK of covalent drugs is often driven by extrahepatic elimination pathways, and therefore conventional approaches to predict human clearance using human hepatocytes or allometric scaling can lead to poor predictive accuracy. We employed a novel physiologically-based PK (PBPK) modeling strategy that accounted for compound-specific determinants of BDTX-189 metabolism and disposition. PK studies following intravenous (IV) and oral (PO) administration were conducted in preclinical species as well as in vitro studies to understand the ADME properties of BDTX-189. These preclinical data formed the basis of a PBPK modeling approach to predict the likely PK profile of BDTX-189 in human. The mechanistic assumptions used in the final models were able to recapitulate the observed animal PK after both IV and PO administration and thus predictions utilizing similar assumptions for human were considered plausible. Taken together with BDTX-189 exposure-response data in mouse models of anti-tumor efficacy, this enabled the prediction of potentially active dose levels in patients. Preclinical PBPK modeling indicated that BDTX-189 would be readily orally absorbed with a short elimination half-life (approximately 2 hours) while maintaining suppression of ErbB pathway biomarkers over the dosing interval, consistent with the irreversible mechanism of action and the desired ‘hit-and-run' PK/pharmacodynamic (PD) profile. Active dose levels in human were projected to be in the 400 - 800 mg QD range, based on the exposure - tumor growth inhibition relationship in multiple mouse PDX models harboring ErbB allosteric mutations. This study demonstrates that a PBPK modeling approach and an understanding of the determinants of clearance can provide an effective framework for preclinical-to-clinical translation. BDTX-189 is currently under clinical evaluation in the ongoing MasterKey-01 trial (NCT04209465), and clinical PK will be reported in due course.
Citation Format: Giorgio Ottaviani, Matthew O'Connor, Alexander Flohr, Darlene Romashko, Alexander Mayweg, Elizabeth Buck, Nigel Waters. Prospective preclinical modeling to estimate clinical pharmacokinetics and doses of BDTX-189, an inhibitor of allosteric ErbB mutations in advanced solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB127.