Cardiotoxicity Associated with Nicotinamide Phosphoribosyltransferase Inhibitors in Rodents and in Rat and Human-Derived Cells Lines.

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein that functions as an enzyme, cytokine, growth factor and hormone. As a target for oncology, NAMPT is particularly attractive, because it catalyzes the rate-limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. Inhibition of NAMPT generally results in NAD depletion, followed by ATP reduction and loss of cell viability. Herein, we describe NAMPT inhibitor (NAMPTi)-induced cardiac toxicity in rodents following short-term administration (2-7days) of NAMPTi's. The cardiac toxicity was interpreted as a functional effect leading to congestive heart failure, characterized by sudden death, thoracic and abdominal effusion, and myocardial degeneration. Based on exposures in the initial in vivo safety rodent studies and cardiotoxicity observed, we conducted studies in rat and human in vitro cardiomyocyte cell systems. Based on those results, combined with human cell line potency data, we demonstrated the toxicity is both on-target and likely human relevant. This toxicity was mitigated in vitro by co-administration of nicotinic acid (NA), which can enable NAD production through the NAMPT-independent pathway; however, this resulted in only partial mitigation in in vivo studies. This work also highlights the usefulness and predictivity of in vitro cardiomyocyte assays using human cells to rank-order compounds against potency in cell-based pharmacology assays. Lastly, this work strengthens the correlation between cardiomyocyte cell viability and functionality, suggesting that these assays together may enable early assessment of cardiotoxicity in vitro prior to conduct of in vivo studies and potentially reduce subsequent attrition due to cardiotoxicity.