Caroline Woodward , Biogen, Cambridge, MA
Himanshu Naik , Biogen, Cambridge, MA
Mark Versavel , Biogen, Cambridge, MA
Lin Xu , Biogen, Cambridge, MA
Xiaopeng Miao , Biogen, Cambridge, MA
Hao Sun , Covance Inc., Madison, WI
Mark Gohdes , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Joi Dunbar , Biogen, Cambridge, MA
Background and aim: BIIB074 ((2S,5R)-5-[4-[(2-fluorophenyl)methoxy]phenyl]pyrrolidine-2-carboxamide) is a Nav1.7-selective, state-dependent sodium channel blocker, currently in development for the treatment of trigeminal neuralgia and other neuropathic pain conditions. In vitro data indicate that BIIB074 is metabolized primarily by uridine diphosphate (UDP)-glucuronosyltransferase(s) (UGTs), while metabolism via cytochrome P450 enzymes plays a minor role. The primary UGT-mediated metabolite of BIIB074 is the N-carbamoyl glucuronide M13. Oxidative metabolites of BIIB074 include the carboxylic acid M14, and the imine carboxylic acid M16. An open-label, single-site, Phase 1 study was conducted to evaluate the absorption, metabolism and excretion of BIIB074 using radiolabeled drug. Methods: Six healthy male subjects received a single, oral dose of BIIB074 200 mg containing ~100 μCi of [14C]-BIIB074 via two capsules on day 1, following an overnight fast of ≥10 hours. Blood, urine and fecal samples were collected daily from each subject until day 9 (192h postdose). If subjects did not meet specified discharge criteria at day 9 (≥90% of radioactive dose recovered or ≤1% of radioactive dose recovered in urine and feces for 2 consecutive 24-h collection intervals), sampling continued up to a maximum of day 14. Total radioactivity in whole blood, plasma, urine and feces was measured using liquid scintillation counting. Plasma and urine concentrations of BIIB074 and its metabolites, M13, M14 and M16, were determined using validated liquid chromatography with tandem mass spectrometric detection methods. Results: BIIB074 was extensively and rapidly absorbed, with median time to maximum concentration observed at 2h. Overall mean radioactivity recovery in urine and feces was 96.4% through 192h postdose, with a mean of 93.2% and 3.2% recovered in urine and in feces, respectively. The majority (91.8%) of the administered radioactivity was recovered in the first 72h postdose, and was primarily associated with BIIB074 metabolites; urinary excretion of unchanged BIIB074 was minor, with 15.0% of the dose excreted as parent drug. The most abundant metabolite excreted in urine was the N-carbamoyl glucuronide metabolite M13, which represented ~40% of the administered BIIB074 dose on a molar basis. M14 contributed to ~26% and M16 <1%. No human-specific metabolites were identified in the current study. BIIB074 was well tolerated and no new safety trends were observed. Conclusions: Among healthy male subjects receiving a single oral dose of BIIB074 200mg containing ~100 μCi of [14C]-BIIB074, BIIB074 was extensively metabolized; M13 was the major metabolite, suggesting UGT glucuronidation was the predominant pathway.