Abstract #5101: Pre-clinical toxicology of triphendiol
Authors: M Saif, D Brown, A Husband
Journal: Cancer Research (2009)

Triphendiol (NV-196) is a low molecular weight isoflavan-like molecule. In vitro and in vivo studies conducted in models of pancreatic and bile duct cancer demonstrate that triphendiol is pro-apoptotic and is active as monotherapy and as a gemcitabine chemosensitizer. Data presented at the 2008 annual ASCO meeting (Abstract# 14615) reported that in a human Phase I clinical study, oral triphendiol demonstrated a good safety profile and successful pharmacokinetics. Triphendiol has been granted orphan drug status by the U.S. Food and Drug Administration (FDA) for pancreatic cancer and cholangiocarcinoma, and for treatment of stage IIb-IV malignant melanoma. Here, we report on the pre-clinical toxicology studies that have been conducted on triphendiol.In hERG binding assays, triphendiol (10 µM) non-significantly inhibited [3H]-astemizole hERG binding by 35%. Triphendiol dose-dependently inhibited hERG tail current (IC50=9.26\#956;M) in a patch clamp assay but the IC50 obtained in this assay is significantly above that seen at steady state levels in human plasma following repeat oral dosing (approximately 5 ng/mL equivalent to 0.014 \#956;M). Triphendiol was non-mutagenic in the bacterial reverse mutation assay (Ames test) and non-clastogenic in the mouse erythrocyte micronucleus assay. Triphendiol toxicology has been evaluated in single and repeat dose GLP studies in the rat and dog for up to 28 days repeat dosing. In the Sprague Dawley rat, lipid vacuolization of the zona fasciculata (100 and 250 mg/kg/day) and decreased width and cellular disorganisation in zona glomerulosa in the adrenals was noted but these changes were reversed after a 21-day recovery period. In the Beagle dog using a 28-day repeat dose regimen, an MTD for orally delivered triphendiol could not be achieved at doses up to 2000 mg/kg/day. There were no toxicologically important changes in clinical signs, body weights, hematology, coagulation time, serum chemistry, urinalysis, gross observations, organ weights or histologic findings for any study animal. As part of this study electocardiography was performed and there were no significant changes to the parameters examined including heart rate and the Q-T segment interval. After oral administration of triphendiol, toxicokinetic analysis on day 27 revealed that the mean Tmax ranged from 0.69 to 2.17 hours for free triphendiol, and 6.67 to 45.33 hr for total (free+conjugated) triphendiol. The AUC values for free triphendiol accounted for 1.30 to 2.09% on Day 27 indicating that exposure to conjugated triphendiol was much greater than exposure to free triphendiol. No accumulation of triphendiol occurred.The data presented here show that triphendiol has an acceptable toxicity profile in rats and dogs, and is without genotoxicity. Previous data have confirmed triphendiol\#8217;s efficacy as a gemcitabine chemosensitizer in pancreatic and bile-duct cancer, and that it has a good safety and pharmacokinetic profile in humans.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5101.