A cross-species translational pharmacokinetic-pharmacodynamic evaluation of core body temperature reduction by the TRPM8 blocker PF-05105679

PF-05105679 is a moderately potent TRPM8 blocker which has been evaluated for the treatment of cold pain sensitivity. The TRPM8 channel is responsible for the sensation of cold environmental temperatures and has been implicated in regulation of core body temperature. Consequently, blockade of TRPM8 has been suggested to result in lowering of core body temperature. As part of the progression to human studies, the effect of PF-05105679 on core body temperature has been investigated in animals. Safety pharmacology studies showed that PF-05105679 reduced core body temperature in a manner that was inversely related to body weight of the species tested (greater exposure to PF-05105679 was required to lower temperature by 1°C in higher species). Based on an allometric (body weight) relationship, it was hypothesized that PF-05105679 would not lower core body temperature in humans at exposures that could exhibit pharmacological effects on cold pain sensation. On administration to humans, PF-05105679 was indeed effective at reversing the cold pain sensation associated with the cold pressor test in the absence of effects on core body temperature.