PHARMACOKINETICS OF SNX-111, A SELECTIVE N-TYPE CALCIUM-CHANNEL BLOCKER, IN RATS AND CYNOMOLGUS MONKEYS

SNX-111, a selective N-type voltage-sensitive calcium channel blocker, is in clinical trials for the treatment of ischemia-induced brain inj ury and chronic pain. Pharmacokinetic studies were conducted in rats a nd cynomologus monkeys to determine the disposition of this compound w hen it is administered for 24 hr by continuous, constant-rate intraven ous infusion. Venous blood samples for determination of SNX-111 plasma levels were collected at regular intervals immediately before, during , and after dosing. Plasma concentrations of SNX-111 equivalents were measured by radioimmunoassay, Pharmacokinetic parameters were derived from plasma SNX-111 concentration-time data using a two-compartment ph armacokinetic model. Results showed close correspondences between phar macokinetic parameters determined for both species. There were no cons istent gender- or dose-related differences in calculated kinetic param eters. In all cases, apparent steady-state plasma SNX-111 concentratio ns were achieved within 2-4 hr of initiating SNX-111 infusion. Steady- state volume of distribution values were similar to 40% of body weight , indicating extravascular dissemination of SNX-111 to both extracellu lar and intracellular fluids. Elimination curves contained two exponen tial components. The fast component (rat t 1/2,alpha = 0.375 hr; monke y t 1/2,alpha = 0.730 hr) accounted for similar to 97% of the unit imp ulse disposition function. The apparent terminal half-life ranged from 4.61 hr (rat) to 6.48 hr (monkey), Current findings constitute the fi rst description of the pharmacokinetics of a member of the omega-conop eptide family of neuronal calcium channel blockers.