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

Abstract

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 GDC-0152 showing adverse signs of a tumor necrosis factor alpha (TNF-α) 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 1.48mg/kg. Similar simulations using rat TD parameters suggest little or no change. Patients given iv doses of GDC-0152 up to 1.48mg/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.

A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma

“…This was especially encouraging because of the concerns related to hypovolemic shock raised by dog toxicology studies. It is clear that dogs are more sensitive to IAP antagonists than humans (23,29). There are several possible explanations for the safety and tolerability profiles exhibited by birinapant in this study as compared with other SMAC mimetics.…”

“…The starting dose of 0.18 mg/m 2 was chosen as this dose level corresponded to onesixth the highest nonseverely toxic dose (HNSTD) in dog, the most sensitive species (23). Dose escalation used a modified Fibonacci sequence; intracohort doses were increased by 100% if no dose-limiting toxicity (DLT) were observed in the first cycle, and were increased either 50 or 33% if a drug-related DLT of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 4) grade 2 AE occurred, depending on the event type and grade.…”

Small-molecule SMAC mimetics as new cancer therapeutics

“…The onset and resolution of these acute toxicities generally tracks with the time course of GDC-0152-induced cytokine [145]. Despite these potential toxicity concerns based upon in preclinical data, patients administered intravenous doses of GDC-0152 up to 1.48 mg/kg showed no signs of a severe TNFα-driven systemic inflammatory response [146] and severe cytokine release syndrome, caused by an acute increase in plasma TNFα and other inflammatory cytokines, has not been reported in patients [142–144]. Similarly, phase I studies for other Smac mimetics have not found a severe TNFα-driven systemic inflammatory response or severe cytokine release syndrome.…”

IAP proteins as targets for drug development in oncology

“…MCP-1 was used as a clinical biomarker for SMs efficiency in clinical programs 133,135. The analysis of the proinflammatory characteristics of cellular Smac-induced cell death suggests that the proinflammatory response elicited by SMs could activate the adaptive antitumor immune response in cancers 136.…”