Sodium Channel (Nav) blockers provide a differentiated mechanism of action in the pharmacotherapy of neuropathic pain, but their use is currently limited by narrow therapeutic indices with respect to CNS side effects, and for some agents, their cardiovascular side effects. Nektar Therapeutics’ technology has been applied to regulate CNS entry of a Nav-inhibitor pharmacophore with validated clinical efficacy and low cardiovascular liability. The in vitro pharmacology of NKTR-171 was characterized against recombinant human Navs and in native rat dorsal root ganglion cells, where NKTR-171 produces a state-dependent block. The analgesic efficacy of NKTR-171 was measured in rat models of persistent pain and neuropathic pain. In the rat formalin and Spinal Nerve Ligation models, acute oral administration of NKTR-171 (30-450 mg/kg) produces dose-dependent analgesic effects, with a maximal efficacy comparable to that of a 100 mg/kg oral dose of pregabalin in both models. However, NKTR-171 exhibited a favorable therapeutic window with respect to CNS side effects. The time spent on a rotarod was not impaired by a dose of NKTR-171 (200 mg/kg p.o.) that was maximally efficacious in the rat formalin model, whereas an equianalgesic dose of pregabalin (100 mg/kg p.o.) reduced the time spent on the rotarod to 30% of baseline values. Pharmacokinetic studies in rats show NKTR-171 to have a low brain:plasma ratio, compared to clinically used Nav blockers. The results of these preclinical studies show that NKTR-171 is a novel Nav blocker that demonstrates comparable analgesic efficacy to pregabalin with reduced CNS side effects. Disclosure: Authors are employees of Nektar Therapeutics.
© 2013 Published by Elsevier Inc.