Abstract 4631: The Cytochrome P450 Inhibitor Fluconazole Increases Plasma Concentrations of R-, and S-Warfarin but not ATI-5923, a Novel VKOR Inhibitor
Warfarin (WARF) is a Vitamin K epoxide reductase (VKOR) inhibitor and oral anticoagulant widely used for prevention and/or treatment of stroke associated with atrial fibrillation. In spite of proven efficacy, WARF therapy is limited by numerous drug-drug interactions (DDIs). Of these, many involve inhibition of it’s cytochrome P450 (CYP) mediated metabolism, leading to increased drug exposure and risk of bleeding. ATI-5923 was created with the goal of producing a VKOR inhibitor that was non-oxidatively hydrolyzed by esterases to an inactive metabolite (ATI-5900) and thereby reduced likelihood of DDIs and maintain the benefits of WARF. We hypothesized that, unlike warfarin the pharmacokinetics (PK) of ATI-5923 is not subject to DDI with the CYP 2C9/3A4 inhibitor fluconazole (FCZ). Two groups (n=10/group) of healthy volunteers were randomized to receive a single equipotent oral doses of either WARF (17.5 mg) or ATI-5923 (50 mg). ATI-5923, ATI-5900, R-WARF and S-WARF concentrations were measured in serial plasma samples collected over a 7 day period and the PK parameters (AUC, Cmax, Tmax and T1/2) were determined. On day 7, subjects were given FCZ (400 mg/day) for 14 days and on day 21, subjects received a second dose of either WARF or ATI-5923 and FCZ was continued for 7 days and the PK study was repeated. Exposure (AUC)for WARF were dramatically increased by FCZ treatment, with the effects being more pronounced on the more active S-isomer: The AUCinf for S-WARF was increased more than 3 fold while this parameter was increased 2 fold for R-warf. Increased exposure appeared to result from reduced clearance: The T1/2 increased from 48 to 104.3 hrs (R-warf) and from 31 to 87.9 hrs (S-warf). No significant effects of FCZ treatment on ATI-5923 or ATI-5900 exposures or clearance were observed. The dramatic effect of the CYP2C9/3A4 inhibitor FCZ on WARF exposure is consistent with the known CYP-mediated clearance of this drug. In the clinical setting, a corresponding increase in WARF exposures would be expected to increase anticoagulant effects and raise the risk of bleeding. In contrast, ATI-5923 which undergoes non-CYP mediated metabolism, is unaffected by FCZ treatment.