The complete bioavailability of asundexian is unaffected by tablet formulation, gastric pH or food

Abstract

Abstract Background Anticoagulation and antiplatelet therapy, mainstays for the prevention of thromboembolic disorders, are associated with an increased bleeding risk. Asundexian, a novel, potent and reversible oral inhibitor of factor XIa, is independent of the extrinsic coagulation pathway and thus not expected to increase bleeding risk. Purpose To determine the absolute bioavailability (FAB), and to assess the impact of gastric pH modulators, tablet formulation, and food on the PK and safety of asundexian. Methods Four studies enrolled healthy White males aged 18–45 years. For FAB (20463), participants received a microdose of 50 μg stable [13C7,15N]-labelled asundexian intravenously (iv) 2 hours after 25 mg asundexian orally in the fasted state. The remaining studies randomized participants to each of 3 treatment sequences. Tablet formulation and food effects were explored in studies 19663 and 21660; participants received asundexian (immediate release [IR] vs amorphous solid dispersion [ASD] phase [Ph] 2 [19663] or ASD Ph 2 vs ASD Ph 3 [21660]) in the fasted states. Food effect was explored using the Ph 2 and Ph 3 tablets. Gastric pH modulators (omeprazole and antacid) were given with asundexian in the fasted state (20459). Blood samples were taken over 72–96 hours post dose. Key PK parameters were area under concentration/time curve (AUC; and AUC/dose [D]) and maximum observed concentration (Cmax; and Cmax/D). FAB was derived as (AUC/D)oral/(AUC/D)iv. Relative bioavailability (FR) was derived from the ratios (ASD Ph 2:IR or ASD Ph 3:ASD Ph 2) of AUC/D and Cmax/D (fasted); gastric pH modulation and food effect were derived from the ratios asundexian+pH modulator:asundexian and fed:fasted of AUC and Cmax, respectively. Results PK data were available for 59 participants. Asundexian was completely bioavailable (FAB, 103.9%). Ph 2 and Ph 3 ASD tablets exhibited a FR of 94.3% and 95.1% for AUC/D compared with the IR or Ph 2 ASD tablet, respectively. Cmax/D results were similar (95.5% and 88.7%, respectively). A high-calorie, high-fat meal reduced AUC and Cmax of asundexian to 91.1% and 78.3%, respectively (ASD Ph 2 tablet), and to 96.9% and 95.1%, respectively (ASD Ph 3 tablet). Coadministration of omeprazole had no influence on the PK of asundexian, whereas antacid slightly reduced AUC and Cmax by 10% and 16%, respectively. Geometric least-squares mean (90% confidence intervals) for the ratios of AUC(/D) and Cmax(/D) by treatment are shown in Figure 1. There were no serious adverse events (AEs) or deaths; most AEs were mild or moderate. Conclusions Orally administered asundexian was almost completely bioavailable. First pass metabolism in the gut and liver does not play an important role in the bioavailability of asundexian; there were no clinically relevant changes due to formulation, food conditions or gastric pH modulation. Results were used to guide dosing recommendations for subsequent Ph 2 (completed) and Ph 3 (planned) studies. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER AG