Oral repeated-dose toxicity studies of BIA 10–2474 in Wistar rat

Publication date: Available online 20 November 2019Source: Regulatory Toxicology and PharmacologyAuthor(s): A. Wallace Hayes, Jerold F. Hardisty, Stephen B. Harris, Yoshimasa Okazaki, Klaus WeberAbstractBIA 10–2474 is a novel fatty acid amide hydrolase (FAAH) inhibitor developed for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10–2474 and four other subjects displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial, we report here the preclinical toxicology studies examining once-a-day oral administration of BIA 10–2474 to male and female Wistar rats. These included a 14-day dose range finding (150, 200 and 250 mg/kg/day), a 4-week study (30, 90 and 150 mg/kg/day) and 13- and 26-week studies (both at 10, 30 and 90 mg/kg/day). The 13- and 26-week studies also included a 4-week recovery arm and a toxicokinetic arm for the parent compound, BIA 10–2474, and the two major metabolites (BIA 10–2445 and BIA 10–2583) were also measured in the 26-week study.At 150 mg/kg and below, all animals survived the scheduled treatment periods although neurological side-effects (abnormal or stiff gait, dragging of fore- or hind-limbs) were seen at 150 mg/kg in both the dose-range finding and 4-week studies. At 90 mg/kg/day, even up to 26-weeks trea...
Source: Regulatory Toxicology and Pharmacology - Category: Toxicology Source Type: research