Two-year carcinogenicity studies with the oral direct thrombin inhibitor ximelagatran in the rat and the mouse.

The results of 18 months mouse and 24 months rat carcinogenicity studies with the oral direct thrombin inhibitor ximelagatran are presented. In the mouse, gavage doses of ximelagatran up to 180 µmol/kg per d produced no neoplastic changes in any of the tissues examined. In the rat, gavage doses up to 240 µmol/kg per d produced multiple macroscopically detectable nodules in the pancreas, which are seen to be focal/multifocal acinar cell hyperplasia and focal/multifocal acinar cell adenoma upon histological evaluation. There were no other treatment-related effects on tumor incidence or distribution in the rat. The studies show a clear species difference in pancreatic effects between the rat and the mouse to long-term treatment with ximelagatran.

Assessment of biomarkers of drug-induced kidney injury in cynomolgus monkeys treated with a triple reuptake inhibitor.

Drug-induced kidney injury (DIKI) results in attrition during drug development; new DIKI urinary biomarkers offer potential to detect and monitor DIKI progression and regression, but frequently only in rats. The triple reuptake inhibitor (TRI) PRC200-SS represents a new class of antidepressants that elevate synaptic levels of serotonin, norepinephrine, and dopamine and is expected to produce more rapid onset and better antidepressant efficacy than single or dual inhibitors. Although preclinical studies and recent clinical trials lend support to this concept of superior efficacy for TRIs, there is little information on the safety profile of this class of compounds. Using histopathology and DIKI biomarkers, in single- and repeat dose toxicological studies in cynomolgus monkeys, PRC200-SS demonstrated dose-proportional kidney toxicity. Characterization of the histopathological lesions, using a combination of immunohistochemistry (IHC) and urinary biomarker analysis, indicated that the compound is a distal tubule and collecting duct toxicant. Segment specificity for the lesions was shown using a newly developed triple IHC combination method with antibodies against calbindin D28, aquaporin 2, and aquaporin 1. Urinary biomarker analyses, using multiplex immunoassays, confirmed a dose-proportional increase in the excretion of calbindin D28 and clusterin in compound-treated monkeys with levels returning to baseline during the drug-free recovery period. These results constitute the validation of distal nephron DIKI biomarkers in the cynomolgus monkey and demonstrate the utility of calbindin D28 and clusterin to monitor the progression of distal nephron DIKI, representing potential early biomarkers of DIKI for the clinic.