Abstract

Carfilzomib, an irreversible proteasome inhibitor, has a favorable safety profile and significant anti-tumor activity in patients with relapsed and refractory multiple myeloma (MM). Here we summarize the clinical pharmacokinetics (PK), metabolism, and drug-drug interaction (DDI) profile of carfilzomib. The PK of carfilzomib, infused over 2-10 min, was evaluated in patients with solid tumors or MM. Metabolites of carfilzomib were characterized in patient plasma and urine samples. In vitro drug metabolism and DDI studies were conducted in human liver microsomes and hepatocytes. A clinical DDI study was conducted in patients with solid tumors to evaluate the effect of carfilzomib on cytochrome (CYP)3A activity. Plasma concentrations of carfilzomib declined rapidly and in a biphasic manner following intravenous administration. The systemic half life was short and the systemic clearance rate was higher than hepatic blood flow. Carfilzomib was mainly cleared by extrahepatic metabolism via peptidase cleavage and epoxide hydrolysis. CYP-mediated metabolism played a minor role, suggesting that co-administration of CYP inhibitors or inducers is unlikely to change its PK profile. Carfilzomib showed direct and time-dependent inhibition of CYP3A in human liver microsome preparations and exposure to carfilzomib resulted in reductions in CYP3A and 1A2 gene expression in cultured human hepatocytes. However, administration of carfilzomib did not affect the PK of midazolam in patients with solid tumors, and there were no safety signals indicative of potential drug interactions. We conclude that the unique PK properties of carfilzomib limit clinically significant DDI.