Details

Autor(en) / Beteiligte

• Tarcha, Eric J
• Chi, Victor
• Muñoz-Elías, Ernesto J
• Bailey, David
• Londono, Luz M
• Upadhyay, Sanjeev K
• Norton, Kayla
• Banks, Amy
• Tjong, Indra
• Nguyen, Hai
• Hu, Xueyou
• Ruppert, Greg W
• Boley, Scott E
• Slauter, Richard
• Sams, James
• Knapp, Brian
• Kentala, Dustin
• Hansen, Zachary
• Pennington, Michael W
• Beeton, Christine
• Chandy, K George
• Iadonato, Shawn P

Titel

Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease

Ist Teil von

• The Journal of pharmacology and experimental therapeutics, 2012-09, Vol.342 (3), p.642-653

Ort / Verlag

United States

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.