Cross-Species Differences in the Preclinical Pharmacokinetics of CT7758, an α4β1/α4β7 Integrin Antagonist

Abstract

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 26 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 Q H ) and associated with a short elimination half-life (£1 hour). This contrast with the dog data which showed a much lower clearance (6% Q H ) and a longer t 1/2 (2.4 hours). The volume of distribution (V z ) 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% Q H ), 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.

Effects of membrane transport activity and cell metabolism on the unbound drug concentrations in the skeletal muscle and liver of drugs: A microdialysis study in rats

“…As shown in Table 2, propranolol, diltiazem, quinidine, memantine, diphenhydramine, and pyrilamine showed high plasma clearance, which approached or exceeded the reported rat hepatic blood flow of 75–90 ml/min/kg 16,17 . The mean values of plasma CL were 97.7, 82.8, 76.4, 60.5, 152, and 167 ml/min/kg, respectively, for diltiazem, propranolol, quinidine, memantine, diphenhydramine, and pyrilamine in rats in this study.…”

“…As shown in Table 2, propranolol, diltiazem, quinidine, memantine, diphenhydramine, and pyrilamine showed high plasma clearance, which approached or exceeded the reported rat hepatic blood flow of 75-90 ml/min/kg. 16,17 The mean values of plasma CL were 97. and 15.0 ml/min/kg, respectively). [24][25][26][27] As shown in our previous study, 6 With the exception of propranolol unbound concentrations in liver, the unbound drug concentrations of all compounds reached a steady state in blood, liver and skeletal muscle within 2 h after the start of infusion.…”

Predicting Oral Drug Absorption: Mini Review on Physiologically-Based Pharmacokinetic Models

“…However, extensive in vivo evaluation in preclinical species can be costly and time consuming. Furthermore, species differences in pharmacokinetics can cause unreliable predictions of oral bioavailability in humans when using in vivo animal data [ 6 , 7 ]. In vitro assays assessing factors such as compound permeability, dissolution, solubility, and metabolic stability offer a more efficient and cost-effective means to evaluate the potential oral bioavailability of large numbers of drug candidates.…”

The Design of Potent, Selective and Drug‐Like RGD αvβ1 Small‐Molecule Inhibitors Derived from non‐RGD α4β1 Antagonists

“…[25] Preliminary work, however, showedt hat severalu rea parentc ompounds had good passive permeability,s uch as 10 (MDCKII-MDR1 P exact 77 nm s À1 ). [25] Preliminary work, however, showedt hat severalu rea parentc ompounds had good passive permeability,s uch as 10 (MDCKII-MDR1 P exact 77 nm s À1 ).…”

“…It is anticipated that the developability of the urea series in vivo could take asimilarp ath to the structurally relatedt emplates of historic a4b1molecules, for which high oral bioavailability required an ester prodrug. [25] Preliminary work, however, showedt hat severalu rea parentc ompounds had good passive permeability,s uch as 10 (MDCKII-MDR1 P exact 77 nm s À1 ). Compound 10 also demonstrated low in vitro clearance in rat and human liver S9 fractions( < 0.6 mL min À1 (g tissue) À1 ), which suggestsareasonable level of metabolic stability (see SI for assay details).…”