Abstract 4386: Administration of nicotinic acid reduces or prevents adverse effects of MPC-9528, a potent and selective Nampt inhibitor
Authors: Mather Gary G. , Belcher Valerie L. , Costa Anna , DeMie Lynn , Roman Orvelin , Fotheringham Lori , Bradford Chad 
Published: June 2012

Background: Inhibition of Nampt in cancer cell lines decreases NAD levels and induces cell death. We evaluate the potential toxicity of MPC-9528, a Nampt inhibitor, and investigate the effects of coadministration of nicotinic acid (NA), the substrate for an alternate pathway leading to NAD formation in normal tissues but lacking in many cancer cells.

Methods: SD rats 8/sex/group were administered MPC-9528 at doses of 0, 10, or 15 mg/kg/day, or 15 mg/kg/day + 200 mg/kg/day of NA. Three additional rats were used to evaluate recovery after 7 days without treatment. Pathology was assessed at scheduled necropsies and PK parameters were determined, organ weights recorded, and selected tissues examined microscopically. Subsequently, CD-1 mice were given single oral doses of MPC-9528 at levels known to be efficacious in xenografts or lethal (75 or 300 mg/kg, respectively). NAD levels and white cell counts were determined. Female rats (n=6) were administered MPC-9528 (15 mg/kg/day) with or without pretreatment with NA (200 mg/kg/day) for 9 days. NAD levels were quantified by LC/MS/MS.

Results: Cmax and AUC in females were approximately five times those in male rats. Two females died in the 10 mg/kg group and 8/11 females in the 15 mg/kg group. There were no deaths in male rats or in females dosed with MPC-9528 and NA. Leukocyte counts were reduced (36.4-77.0%) for all groups compared to controls. The reduction for rats treated concurrently with NA was less than groups treated with MPC-9528 alone. Leukocyte counts partially recovered 7 days off drug. There were no significant changes in clinical chemistry at any dose in male rats. AST and CPK were increased in a single female compared to controls. Albumin and total protein were reduced in females treated at 10 or 15 mg/kg/day. Thymus weights were reduced in all treated groups and spleen weights were reduced in females. These changes were not observed at the recovery sacrifice. Testis weight was reduced at both terminal and recovery in MPC-9528 treated males. Lymphoid depletion was noted on histopath. Clinical pathology, organ weight, and histopath changes were either reduced in severity or prevented by concurrent NA. NAD levels in mice given a single dose of 75 mg/kg were reduced &gt;95% and white counts were reduced from a mean of 2.2 × 106/mL to 0.2 × 106/mL by Day 6. Lethality of a 300 mg/kg single dose in mice was completely prevented by coadministration of 1000 mg/kg NA. Similarly, NAD levels in rat blood decreased &gt;50% by Day 6 in females administered MPC-9528 (15 mg/kg/day), however, with concurrent NA, NAD levels were reduced less than 30%.

Conclusion: Coadministration of NA prevented or reduced the severity of adverse effects associated with daily administration of higher doses of MPC-9528. These data suggest that coadministration of NA has the potential to increase the therapeutic margin and to abrogate adverse clinical events in future clinical studies of MPC-9528.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4386. doi:10.1158/1538-7445.AM2011-4386