Pharmacokinetic-Pharmacodynamic Modeling of the Immunomodulating Agent Susalimod and Experimentally Induced Tumor Necrosis Factor-a Levels in the Mouse

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-a (TNF-a). 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-a. The concentration-effect relationship was explored by modeling the data from all dose levels simultaneously using specially written program models, i.e., a threecompartment 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-a synthesis during ;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 (IC50) of susalimod could be estimated to 293 mM. In conclusion, susalimod decreased the LPS-induced TNF-a mouse serum levels in a concentrationrelated manner. The compound is suggested to inhibit the synthesis of TNF-a. The integrated pharmacokinetic-pharmacodynamic model estimated the in vivo potency of susalimod in the mouse to be 293 mM. The current knowledge about the mechanism of action of disease-modifying antirheumatic drugs (DMARDs) involves inhibition of the production of proinflammatory cytokines (Bondeson, 1997). In particular, tumor necrosis factor-a (TNF-a) has been demonstrated to be of pivotal importance in rheumatoid arthritis (RA). The pharmacological effect of anti-inflammatory and immunomodulating agents is commonly studied with bacterial lipopolysaccharide (LPS) (Remick et al., 1989; Shapira et al., 1996) because administration of LPS into experimental animals leads to a rapid induction of macrophage-monocyte TNF-a synthesis and develops similar pathophysiological changes to those of an inflammatory response. Hence, the effect of DMARDs on LPS-induced elevated TNF-a exposure serves as a useful pharmacodynamic (PD) model for these types of agents. In this study, we investigated the pharmacological action of susalimod, a metabolically stable chemical analog of sulfasalazine designed within a drug development program for the treatment of RA. The pharmacokinetics (PK) of susalimod has been investigated in various animal species (Påhlman et al., 1998). Its PK profile is characterized by an extensive biliary excretion, mainly as unchanged parent drug. Furthermore, the compound is very highly bound to plasma albumin and has a small volume of distribution. In contrast to previously reported studies, which to our knowledge have only sought to describe a dose-response relationship, we have tried to establish a concentration-effect relationship between a compound (susalimod) and cytokine se-