title: 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.
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA. wong.harvey@gene.com
authors: Harvey
authors: H
authors: Wong
authors: Nageshwar R
authors: NR
authors: Budha
authors: Kristina
authors: K
authors: West
authors: Elizabeth
authors: E
authors: Blackwood
authors: Joseph A
authors: JA
authors: Ware
authors: Ron
authors: R
authors: Yu
authors: Walter C
authors: WC
authors: Darbonne
authors: Stephen E
authors: SE
authors: Gould
authors: Ronald
authors: R
authors: Steigerwalt
authors: Rebecca
authors: R
authors: Erickson
authors: Cornelis E A C
authors: CE
authors: Hop
authors: Patricia
authors: P
authors: LoRusso
authors: S Gail
authors: SG
authors: Eckhardt
authors: Andrew
authors: A
authors: Wagner
authors: Iris T
authors: IT
authors: Chan
authors: Michael
authors: M
authors: Mamounas
authors: John A
authors: JA
authors: Flygare
authors: Wayne J
authors: WJ
authors: Fairbrother
mesh_terms: D000818:Animals; D019540:Area Under Curve; D061945:Caspase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D003510:Cyclohexanes / Q000493:pharmacokinetics / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006207:Half-Life; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D011758:Pyrroles / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D061945:Caspase Inhibitors; D003510:Cyclohexanes; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D011758:Pyrroles; C579046:GDC-0152