RT Journal Article SR Electronic T1 Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 642 OP 653 DO 10.1124/jpet.112.191890 VO 342 IS 3 A1 Tarcha, Eric J. A1 Chi, Victor A1 Muñoz-Elías, Ernesto J. A1 Bailey, David A1 Londono, Luz M. A1 Upadhyay, Sanjeev K. A1 Norton, Kayla A1 Banks, Amy A1 Tjong, Indra A1 Nguyen, Hai A1 Hu, Xueyou A1 Ruppert, Greg W. A1 Boley, Scott E. A1 Slauter, Richard A1 Sams, James A1 Knapp, Brian A1 Kentala, Dustin A1 Hansen, Zachary A1 Pennington, Michael W. A1 Beeton, Christine A1 Chandy, K. George A1 Iadonato, Shawn P. YR 2012 UL http://jpet.aspetjournals.org/content/342/3/642.abstract AB 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 high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an 111In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-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 monkeys. 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 to 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.