Pharmacological validation of a novel nonhuman primate measure of thermal responsivity with utility for predicting analgesic effects

Abstract

IntroductionThe development of novel analgesics to treat acute or chronic pain has been a challenge due to a lack of translatable measurements. Preclinical end points with improved translatability are necessary to more accurately inform clinical testing paradigms, which may help guide selection of viable drug candidates.MethodsIn this study, a nonhuman primate biomarker which is sensitive to standard analgesics at clinically relevant plasma concentrations, can differentiate analgesia from sedation and utilizes a protocol very similar to that which can be employed in human clinical studies is described. Specifically, acute heat stimuli were delivered to the volar forearm using a contact heat thermode in the same manner as the clinical setting.ResultsClinically efficacious exposures of morphine, fentanyl, and tramadol produced robust analgesic effects, whereas doses of diazepam that produce sedation had no effect.ConclusionWe propose that this assay has predictive utility that can help improve the probability of success for developing novel analgesics.

Na v 1.7 target modulation and efficacy can be measured in nonhuman primate assays

“…Because of the limited availability of NHPs for the anesthetized studies, C-fiber microneurography, TT, and olfactory fMRI, they were performed in a nonblinded fashion with an adaptive design to reduce the number of animals required. A decision on futility was made after each dose, with numbers of animals being increased only when an effect was observed and numbers were increased to a achieve a sample size sufficient to achieve statistical significance based on previous studies (31,59). In addition, for microneurography, animals were randomly assigned from a pool of animals slated to be euthanized.…”

“…A clinically translatable behavioral assay that measures heat-induced pain-like behaviors in healthy NHPs was previously described (31).…”

“…Therefore, the purpose of the work detailed here was to develop translational assays in nonhuman primates (NHPs) to guide anticipated human dose calculations and measure the degree of target modulation in the clinic to enable the interpretation of clinical proof-of-concept studies. Three in vivo assays were back-translated from the clinic and established in NHPs: microneurography, to assess compound effects on AP propagation (29) in unmyelinated afferents; threshold tracking (TT), to assess compound effects on the excitability of myelinated afferents (30); and an acute test of heat nociception using equipment used for clinical studies (31). A fourth assay, a functional magnetic resonance imaging (fMRI) assay to study compound effects on olfactory function, was also established in NHPs (32).…”

Application of Pharmacokinetic-Pharmacodynamic Modeling to Inform Translation of In Vitro NaV1.7 Inhibition to In Vivo Pharmacological Response in Non-human Primate

“…Thermode testing was performed in NHPs as outlined in Vardigan et al . 2018 ( 22 ). Briefly, animals were chaired with their arms restrained against the front horizontal panel using umbilical tape.…”

The Opioid Crisis and the Future of Addiction and Pain Therapeutics

“…Using these principles, translatable preclinical models were developed for Merck's novel selective Na v 1.7 inhibitors. Assays were back-translated from the clinic to primate models; for example, primate assays of acute nociception to a noxious thermal stimulus (Vardigan et al, 2018) and microneurography were established. Furthermore, an isoamyl acetate-induced biomarker assay was developed to monitor olfactory bulb activity with functional magnetic resonance imaging (MRI) (Zhao et al, 2016).…”