Dogs Are More Sensitive to Antagonists of Inhibitor of Apoptosis Proteins Than Rats and Humans: A Translational Toxicokinetic/Toxicodynamic Analysis

Inhibitor of apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. GDC-0152 is a potent and selective IAP antagonist being developed as an anticancer agent. In preclinical safety studies, dogs were particularly sensitive to GDC0152 showing adverse signs of a tumor necrosis factor alpha (TNFα) driven systemic inflammatory response, related to cellular IAP degradation and activation of NFκB signaling, at lower exposures compared with rat. In addition, downstream increases in systemic levels of cytokines and chemokines, such as monocyte chemotactic protein-1 (MCP-1), were observed. A semimechanistic population toxicokinetic/toxicodynamic (TK/TD) model incorporating transit compartments was used to fit MCP-1 plasma concentrations from rats or dogs given iv GDC-0152 doses. Estimated TD parameters inferred that lower GDC-0152 plasma concentrations triggered more severe increases in plasma MCP-1 in dogs compared with rats. Human simulations performed using dog TD parameters and human pharmacokinetics predicted 300–2400% increases of MCP-1 in humans at iv doses from 0.76 to 1.48 mg/kg. Similar simulations using rat TD parameters suggest little or no change. Patients given iv doses of GDC-0152 up to 1.48 mg/kg iv showed no substantial increases in systemic MCP-1 or signs of a severe TNF-α driven systemic inflammatory response. Emerging clinical data reported for other IAP antagonists are consistent with our observations. Taken together, the data suggest dogs are more sensitive to IAP antagonists compared with humans and rats. This study illustrates how TK/TD analysis can be utilized to quantitatively translate and context an identified preclinical safety risk in dogs to humans. Inhibitor of apoptosis (IAP) proteins are involved in the regulation of programmed cell death or apoptosis. They were first identified in baculoviruses where they function to suppress host cell death responses during viral infection (Flygare and Fairbrother, 2010; Varfolomeev and Vucic, 2011). IAP proteins suppress apoptosis, in part, by inhibiting activated cytosolic cysteine/aspartate-specific proteases (caspases) that are critical for its execution (Flygare and Fairbrother, 2010; Varfolomeev and Vucic, 2011). The mammalian family of IAP proteins includes X-linked IAP (XIAP), cellular IAP 1 and 2 (cIAP1 and cIAP2), and melanoma IAP (ML-IAP). Of the IAP proteins, only XIAP directly inhibits effector caspases-3 and -7, which execute the apoptotic death program. XIAP also indirectly inhibits effector-caspase activity via inhibition of the initiator caspase-9. ML-IAP and cIAPs directly antagonize second mitochondria-derived activator of caspase/direct IAP-binding protein with low pI (Smac/DIABLO), an endogenous IAP antagonist that acts by blocking XIAP-mediated inhibition of caspases. cIAPs have an additional role of preventing death receptor (e.g., tumor necrosis factor alpha [TNF-α], Fas, DR4, and DR5) mediated activation of initiator caspase-8, thereby stopping downstream activation of effector caspases-3 and -7. Finally, cIAPs positively regulate canonical NF-κB signaling and negatively regulate noncanonical NF-κB signaling and induction of NF-κB target genes, including TNF-α. IAP proteins are frequently overexpressed in cancer cells where they serve as regulators of cancer cell survival and are often indicators of poor prognosis (Vucic and Fairbrother, 2007). Conversely, inhibition of IAP proteins has been shown to sensitize cancer cells to proapoptotic anticancer agents. Thus,