Sonia Roberts

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

Abstract 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. Graphical abstract No caption available.

In vitro secondary pharmacological profiling: An IQ-DruSafe industry survey on current practices

INTRODUCTION In 2015, IQ DruSafe conducted a survey of its membership to identify industry practices related to in vitro off target pharmacological profiling of small molecules. METHODS An anonymous survey of 20 questions was submitted to IQ-DruSafe representatives. Questions were designed to explore screening strategies, methods employed and experience of regulatory interactions related to in vitro secondary pharmacology profiling. RESULTS The pharmaceutical industry routinely utilizes panels of in vitro assays to detect undesirable off-target interactions of new chemical entities that are deployed at all stages of drug discovery and early development. The formats, approaches and size of panels vary between companies, in particular i) choice of assay technology; ii) test concentration (single vs. multiple concentrations) iii) rationale for targets and panels selection (taking into account organizational experience, primary target, therapeutic area, availability at service providers) iv) threshold level for significant interaction with a target and v) data interpretation. Data are generated during the early phases of drug discovery, principally before in vivo GLP studies (i.e., hit-to-lead, lead optimization, development candidate selection) and used to contextualize in vivo non-clinical and clinical findings. Data were included in regulatory documents, and around half of respondents experienced regulatory questions about the significance of the results. CONCLUSION While it seems that in vitro secondary pharmacological profiling is generally considered valuable across the industry, particularly as a tool in early phases of drug discovery for small molecules, there is only loose consensus on testing paradigm, the required interpretation and suitable follow up strategies to fully understand potential risk.