Abstract

The novel wound-healing biologic EPICERTIN, a recombinant analog of cholera toxin B subunit, is in early development for the management of ulcerative colitis. This study established for the first time the pharmacokinetics (PK), bioavailability (BA) and acute safety of EPICERTIN in healthy and dextran sodium sulfate-induced colitic mice and healthy rats. For PK and BA assessments, single administrations of various concentrations of EPICERTIN were given intravenously (iv) or intrarectally (ir) to healthy and colitic C57BL/6 mice and to healthy Sprague Dawley rats. After iv administration to healthy animals, the drug's plasma half-life (t_1/2) for males and females was 0.26 and 0.3 h in mice, and 19.4 and 14.5 h in rats, respectively. After ir administration, drug was detected at very low levels in only 4 samples of mouse plasma, with no correlation to colon epithelial integrity. No drug was detected in rat plasma. A single ir dose of 0.1 µM (0.6 µg/mouse) EPICERTIN significantly facilitated the healing of damaged colonic epithelium as determined by disease activity index and histopathological scoring, while 10-fold higher or lower concentrations showed no effect. For acute toxicity evaluation, healthy rats were given a single ir administration of various doses of EPICERTIN with sacrifice on Day 8, recording body weight, morbidity, mortality, clinical pathology and gross necropsy observations. There were no drug-related effects of toxicological significance. The NOAEL (ir) in rats was determined to be 5 µM (307 µg/animal, or 5.2 µg drug/cm² of colorectal surface area), which is 14-times the anticipated ir-delivered clinical dose.

Significance Statement EPICERTIN is a candidate wound-healing biologic for the management of ulcerative colitis. This study determined for the first time the intravenous (iv) and intrarectal (ir) pharmacokinetics and bioavailability of the drug in healthy and colitic mice and healthy rats, and its acute safety in a dose-escalation study in rats. An initial therapeutic dose in colitic mice was also established. EPICERTIN delivered ir was minimally absorbed systemically, was well tolerated, and induced epithelial wound-healing topically at a low dose.