title: Cross-Species Differences in the Preclinical Pharmacokinetics of CT7758, an α4β1/α4β7 Integrin Antagonist.
abstract: CT7758, a carboxylate containing α4β1/α4/β7 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-to-medium permeability in Caco-2 cells (≤1.3 × 10(-6) 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 CT7758.
authors.affiliation: UCB Pharma SA, Investigative ADME (H.C., V.M., B.G.), Bioanalytical Sciences (L.S.), Laboratory Animal Services (D.B.), Braine l'Alleud, Belgium; Strategic DMPK Support, Braine l'Alleud, Belgium (J.M.N.); and Biogen Idec, Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, Massachusetts (C.P.) Hugues.Chanteux@UCB.com.
authors.forename: Hugues
authors.initials: H
authors.lastname: Chanteux
authors.affiliation: UCB Pharma SA, Investigative ADME (H.C., V.M., B.G.), Bioanalytical Sciences (L.S.), Laboratory Animal Services (D.B.), Braine l'Alleud, Belgium; Strategic DMPK Support, Braine l'Alleud, Belgium (J.M.N.); and Biogen Idec, Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, Massachusetts (C.P.).
authors.forename: Ludovicus
authors.initials: L
authors.lastname: Staelens
authors.affiliation: UCB Pharma SA, Investigative ADME (H.C., V.M., B.G.), Bioanalytical Sciences (L.S.), Laboratory Animal Services (D.B.), Braine l'Alleud, Belgium; Strategic DMPK Support, Braine l'Alleud, Belgium (J.M.N.); and Biogen Idec, Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, Massachusetts (C.P.).
authors.forename: Valérie
authors.initials: V
authors.lastname: Mancel
authors.affiliation: UCB Pharma SA, Investigative ADME (H.C., V.M., B.G.), Bioanalytical Sciences (L.S.), Laboratory Animal Services (D.B.), Braine l'Alleud, Belgium; Strategic DMPK Support, Braine l'Alleud, Belgium (J.M.N.); and Biogen Idec, Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, Massachusetts (C.P.).
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gerin
authors.affiliation: UCB Pharma SA, Investigative ADME (H.C., V.M., B.G.), Bioanalytical Sciences (L.S.), Laboratory Animal Services (D.B.), Braine l'Alleud, Belgium; Strategic DMPK Support, Braine l'Alleud, Belgium (J.M.N.); and Biogen Idec, Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, Massachusetts (C.P.).
authors.forename: David
authors.initials: D
authors.lastname: Boucaut
authors.affiliation: UCB Pharma SA, Investigative ADME (H.C., V.M., B.G.), Bioanalytical Sciences (L.S.), Laboratory Animal Services (D.B.), Braine l'Alleud, Belgium; Strategic DMPK Support, Braine l'Alleud, Belgium (J.M.N.); and Biogen Idec, Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, Massachusetts (C.P.).
authors.forename: Chandra
authors.initials: C
authors.lastname: Prakash
authors.affiliation: UCB Pharma SA, Investigative ADME (H.C., V.M., B.G.), Bioanalytical Sciences (L.S.), Laboratory Animal Services (D.B.), Braine l'Alleud, Belgium; Strategic DMPK Support, Braine l'Alleud, Belgium (J.M.N.); and Biogen Idec, Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, Massachusetts (C.P.).
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Nicolas
mesh_terms: D000818:Animals; D004285:Dogs; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051381:Rats; D013045:Species Specificity; D013141:Spiro Compounds / Q000493:pharmacokinetics*
chemical_list: C000607551:CT7758; D039041:Integrin alpha4beta1; D016023:Integrins; D013141:Spiro Compounds; C071777:integrin alpha4beta7; D010649:Phenylalanine