Dmd064436 1381..1391

CT7758, a carboxylate containing a4b1/a4/b7 integrin antagonist, was characterized for its pharmacokinetic profile in various in vitro and in vivo assays in support of clinical development. The oral bioavailability of CT7758 was 4% in mice, 2% in rats, 7–55% in dogs, and 0.2% in cynomolgus monkeys. The low bioavailability in rodents and monkey results from low intestinal absorption as evidenced by a low fraction absorbed in the rat portal vein model (3%), low-tomedium permeability in Caco-2 cells (£1.3 3 10 cm/s) with evidences of polarized efflux, and high polar surface area (104 Å). In rodents and cynomolgus monkeys, the total plasma clearance was moderate to high (‡50% hepatic blood flow QH) and associated with a short elimination half-life (£1 hour). This contrast with the dog data which showed a much lower clearance (6% QH) and a longer t1/2 (2.4 hours). The volume of distribution (Vz) also varied significantly across species with value of 5.5, 2.8, 0.24, and 0.93 l/kg in mouse, rat, dog, and cynomolgus monkey, respectively. In vitro assays demonstrated that active hepatic uptake accounted for most of the in vivo clearance and was the source of the large species variability. In vitro uptake assays predicted a total plasma clearance in humans in the low range (33% QH), a finding subsequently confirmed in the clinic. Assays in OAPT1B1-transfected cells demonstrated active uptake transport through this transporter. The prospect of limited absorption in human prompted the synthesis an ethyl ester prodrug, CDP323, which demonstrated higher in vitro permeability, increased oral bioavailability, as well as efficient in vivo release of its active moiety