Society of Toxicologic Pathology Neuropathology Interest Group Article: Neuropathologic Findings in Nonhuman Primates Associated With Administration of Biomolecule-Based Test Articles.

The increasing specificity of novel druggable targets coupled with the complexity of emerging therapeutic modalities for treating human diseases has created a growing need for nonhuman primates (NHPs) as models for translational drug discovery and nonclinical safety assessment. In particular, NHPs are critical for investigating potential unexpected/undesired on-target and off-target liabilities associated with administration of candidate biotherapeutics (nucleic acids, proteins, viral gene therapy vectors, etc.) to treat nervous system disorders. Nervous system findings unique to or overrepresented in NHPs administered biomolecule-based ("biologic") test articles include mononuclear cell infiltration in most neural tissues for all biomolecule classes as well as neuronal necrosis with glial cell proliferation in sensory ganglia for certain viral vectors. Such test article-related findings in NHPs often must be differentiated from procedural effects (e.g., local parenchymal or meningeal reactions associated with an injection site or implanted catheter to administer a test article directly into the central nervous system) or spontaneous background findings (e.g., neuronal autophagy in sensory ganglia).

Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor.

Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease. Daprodustat's biological activity simulates components of the natural response to hypoxia; inhibition of PHDs results in HIF stabilization and modulation of HIF-controlled gene products, including erythropoietin. The carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were administered. The mouse study also included evaluation of daprodustat's 3 major circulating human metabolites. There were no neoplastic findings that were considered treatment related in either study. Exaggerated pharmacology resulted in significantly increased red cell mass and subsequent multiorgan congestion and secondary non-neoplastic effects in both species, similar to those observed in chronic toxicity studies. In rats, these included aortic thrombosis and an exacerbation of spontaneous rodent cardiomyopathy, which contributed to a statistically significant decrease in survival in high-dose males (group terminated in week 94). Survival was not impacted in mice at any dose. Systemic exposures (area under the plasma concentration-time curve) to daprodustat at the high doses in rats and mice exceed predicted maximal human clinical exposure by ≥143-fold. These results suggest that daprodustat and metabolites do not pose a carcinogenic risk at clinical doses.

Eugenol anesthesia in African clawed frogs (Xenopus laevis) of different body weights.

The objective of this prospective study was to determine the duration of anesthesia in Xenopus laevis frogs of different body weights relative to exposure time in a eugenol (350 microL/L) bath. Two groups of 5 female frogs each weighing 7.5 +/- 2.1 g (small frogs) or 29.2 +/- 7.4 g (medium frogs) were used. The acetic acid test (AAT), withdrawal reflex, righting reflex, heart rate, and blood oxygen saturation were used to evaluate CNS depression after eugenol bath administration. No responses to the AAT, withdrawal reflex, and righting reflex were seen for 1 h (small frogs) or 0.5 h (medium frogs) after immersion in a eugenol bath for 5 or 10 min, respectively. Oxygen saturation was not affected by anesthesia, but heart rate was depressed for as long as 1 h in both groups of frogs. Surgical anesthesia evaluated by using skin and abdominal incisions revealed that small frogs were anesthetized for a maximum of 15 min compared with 30 min in medium frogs. Frogs showed no ill effects 24 h after eugenol bath administration. These results suggest that body weight is an important parameter to consider when using a eugenol bath for anesthesia of Xenopus frogs.