Susalimod

Abstract: Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long‐term administration of the compound. Dose‐related bile duct hyperplasia appeared only in dogs at doses ≥75 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mg/kg/day respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, ≥90%, mainly as non‐conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 μmol/l was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were ≤7000 μmol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (Påhlman et al. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.

The main objective of this study was to explore the concentration-effect relationship between the immunomodulating agent susalimod and lipopolycaccharide (LPS)-induced elevated serum levels of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Bacterial LPS (1 mg/kg) was given i.p. along with different doses of susalimod (0, 25, 50, 100, and 200 mg/kg) to female CD-1 mice. Blood samples were drawn at different time points (15-300 min), and serum was analyzed with respect to susalimod and TNF-alpha. The concentration-effect relationship was explored by modeling the data from all dose levels simultaneously using specially written program models, i.e., a three-compartment pharmacokinetic model, including biliary excretion, and an indirect mechanistically based pharmacodynamic model. The models, which were successfully fitted to the experimental data, showed that LPS induced the TNF-alpha synthesis during approximately 70 min and that during this time course, the synthesis rate was governed by the serum phamacokinetics of susalimod. Because the results supported the assumption that the maximum inhibitory effect was equal to full inhibition of the synthesis, the in vivo potency (IC(50)) of susalimod could be estimated to 293 microM. In conclusion, susalimod decreased the LPS-induced TNF-alpha mouse serum levels in a concentration-related manner. The compound is suggested to inhibit the synthesis of TNF-alpha. The integrated pharmacokinetic-pharmacodynamic model estimated the in vivo potency of susalimod in the mouse to be 293 microM.