The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic - pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated HPLC-MS/MS method to measure the peptide's concentration in plasma. These results were compared with SPECT/CT data collected with an 111In-DOTA-conjugate of ShK-186 to assess whole blood pharmacokinetic parameters as well as the peptide's absorption, distribution and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site resulting in blood concentrations above the Kv1.3 channel-blocking IC50 value for up to 7 days in monkey. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis and pristane-induced arthritis rat models, a single dose of ShK-186 every 2-5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.
- autoimmune disorders
- pharmacokinetic / pharmacodynamic modeling
- voltage-gated potassium channels
- Received January 18, 2012.
- Revision received May 22, 2012.
- Accepted May 23, 2012.
- The American Society for Pharmacology and Experimental Therapeutics