Abstract 2607: The benefits of irreversibility: Infusion administration of carfilzomib results in potent proteasome inhibition and improved safety in animals
Authors: Jiang Jing , Kirk Christopher J. , Muchamuel Tony , Lee Susan 
Published: June 2012

Carfilzomib (CFZ) is a tetrapeptide epoxyketone-based inhibitor whose primary target is the chymotrypsin-like (CT-L) activity of the 20S proteasome. In clinical trials, intravenous (IV) bolus administration of carfilzomib has shown promising anti-tumor activity in multiple myeloma (MM), including patients relapsed and/or refractory to bortezomib. CFZ is a time-dependent and irreversible inhibitor, suggesting that target inhibition in vivo is likely a result of total dose administered and not steady state or maximum plasma concentration (Cmax). In order to determine if the method of delivery would affect the pharmacodynamics (PD) and toxicity of carfilzomib, we performed a series of experiments in rats. When delivered as an IV bolus or 30-minute infusion, a dose of 8 mg/kg resulted in ≥90% inhibition of the CT-L activity of the proteasome in whole blood and in all analyzed tissues (adrenal, lung, heart, and liver). Inhibition of the trypsin-like (T-L) and caspase-like (C-L) activity of the proteasome was ≥80% and ≥60%, respectively, was indistinguishable between the 2 groups. Despite an identical PD profile, infusion administration was significantly better tolerated than bolus. In the bolus group mortality was 44% (14 of 32) and the remaining animals displayed clinical signs of dyspnea, lethargy and poor blood perfusion to the extremities. None of the 24 animals receiving an infusion administration of CFZ died or were euthanized for humane reasons. A dose of 0.5 mg/kg bortezomib (BTZ), delivered as an IV bolus, produced similar clinical signs and mortality rates as bolus CFZ in rats. This result enabled us to determine which toxicity findings were target mediated. Interestingly, this dose of BTZ resulted in similar levels of inhibition of the CT-L (≥90%) but substantially less inhibition of T-L activity (≤20%) and slightly greater inhibition in C-L activity (≥80%) in blood and tissues. Bolus administration of either CFZ or BTZ resulted in 3 – 6-fold increases in blood urea nitrogen (BUN) and serum creatinine, while infusion administration of CFZ resulted in only a modest increase in BUN and no changes in creatinine levels. Other changes, such as a transient decrease in platelets, were not affected by the method of delivery of carfilzomib. These data suggest that bolus administration of either CFZ or BTZ in rats produced sequelae including pulmonary and cardiovascular function changes, renal azotemia and death and these toxicities are likely Cmax-related. However, because of its irreversible mechanism of proteasome inhibition, CFZ can be safely administered as an infusion resulting in profound proteasome inhibition in blood and tissues. The improved safety of infusion administration seen in these studies provides rationale for clinical application of infusion administration of CFZ in patients with MM.

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 2607. doi:10.1158/1538-7445.AM2011-2607