Metabolism and Disposition of Betrixaban and Its Lack of Interaction with Major CYP Enzymes

• Published in: Blood 2012-11, Vol.120 (21), p.2266-2266
• Main Authors: Hutchaleelaha, Athiwat, Ye, Christine, Song, Yonghong, Lorenz, Todd, Gretler, Daniel, Lambing, Joseph L
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.2266.2266

Abstract 2266 Betrixaban is a once daily oral Factor Xa inhibitor being investigated in a Phase 3 clinical trial to prevent venous thromboembolism in acute medically ill patients (APEX Study). Mass balance, metabolite profile and interaction with major CYP enzymes were evaluated in this study. Portola study 06–005 was an open-label, single-dose, mass-balance and metabolic profiling study using 14C-labeled betrixaban in 5 healthy male volunteers. Each subject received a single oral solution containing 40 mg of betrixaban labeled with 100 μCi of 14C. Blood samples were taken serially over a 168-hour interval. Urine samples and fecal samples were collected during the 7–14 day confinement period. Subjects were discharged from the unit when at least one of the following criteria were met: 90% of the radioactivity was recovered in urine and feces, daily excreted radioactivity was 1% or less of administered dose on two consecutive days, or subject reached 336 hours (14 days) post dose. The plasma concentration equivalents of total radioactivity increased rapidly following dosing with a mean peak of 31.69 ng eq/mL occurring at 3.5 hours post-dose. AUC and half-life could not be calculated as radioactivity in plasma could only be detected up to 6 hours post dose. Terminal elimination half life determined in other clinical pharmacology studies was 37 hours. Total radioactivity recovered from urine and feces was approximately 96% (range 92% to 99%), with the majority of 14C recovery in feces (82% to 89% of the dose). The 14C dose recovered in urine, composed of betrixaban and inactive metabolites, ranged from 6% to 13%. The metabolic profile of betrixaban was determined in plasma, urine and feces. Unchanged betrixaban was the predominant component found in human plasma and excreta, accounting for 85.3% of the dose excreted in urine and feces. The major biotransformation pathway for betrixaban was hydrolysis to form PRT062802 and PRT062803, a non-14C labeled metabolite (Figure 1). PRT062803 can be demethylated to form PRT062799 or hydroxylated to form PRT062982. PRT062982 is further conjugated with sulfate to form PRT063069. Both PRT062802 and PRT063069 were major circulating metabolites in human plasma with AUC of 34% and 24% that of betrixaban, respectively. PRT062802 was the only prominent metabolite detected in human urine and feces. In addition to hydrolysis metabolites, two CYP-mediated metabolites, O-desmethyl betrixaban (PRT058326) and N-desmethyl betrixaban (