Pharmacokinetic-Pharmacodynamic Modeling of the Immunomodulating Agent Susalimod and Experimentally Induced Tumor Necrosis Factor-α Levels in the Mouse
Abstract
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-α (TNF-α). 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-α. 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-α 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 μM. In conclusion, susalimod decreased the LPS-induced TNF-α mouse serum levels in a concentration-related manner. The compound is suggested to inhibit the synthesis of TNF-α. The integrated pharmacokinetic-pharmacodynamic model estimated the in vivo potency of susalimod in the mouse to be 293 μM.
Footnotes
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Send reprint requests to: Peter Gozzi, Pharmacia & Upjohn AB, SE-11287 Stockholm, Sweden. E-mail:peter.gozzi{at}eu.pnu.com
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↵1 Department of Pharmacology, Pharmacia & Upjohn AB, SE-751 82, Uppsala, Sweden.
- Abbreviations:
- DMARD
- disease-modifying antirheumatic drug
- PK
- pharmacokinetic
- TNF-α
- tumor necrosis factor-α
- RA
- rheumatoid arthritis
- LPS
- lipopolysaccharide
- PD
- pharmacodynamic
- IL
- interleukin
- ka
- absorption rate (first-order) of drug
- CLbile
- bile clearance of drug
- C
- serum concentration of drug
- CLt
- distribution clearance of drug
- Ct
- extravascular concentration of drug
- Vc
- volume of distribution, serum compartment
- Agut
- amount of drug in the gut
- ATNF-α
- amount of TNF-α intracellularly
- CTNF-α
- serum concentration of TNF-α
- I
- inhibitory effect intensity of drug
- Vt
- volume of distribution, extravascular compartment
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- Received October 6, 1998.
- Accepted June 14, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
