Abstract
Carfilzomib (also known as PR-171) is a selective, irreversible proteasome inhibitor that has shown encouraging results in clinical trials in multiple myeloma. In this study, the pharmacokinetics, pharmacodynamics, metabolism, distribution and excretion of carfilzomib in Sprague Dawley rats were characterized. Following intravenous administration, the plasma concentration of carfilzomib declined rapidly in a biphasic manner. Carfilzomib displayed high plasma clearance (195 to 319 mL/min/kg), a short terminal half life (5-20 minutes) and rapid and wide tissue distribution in rats. The exposure to carfilzomib (Cmax and AUC) increased dose proportionally from 2 to 4 mg/kg but less than dose proportionally from 4 to 8 mg/kg. The high clearance was predominantly mediated by extrahepatic metabolism through peptidase cleavage and epoxide hydrolysis. Carfilzomib was excreted mainly as metabolites resulting from peptidase cleavage. Carfilzomib and its major metabolites in urine and bile accounted for about 26% and 31% of the total dose, respectively, for a total of 57% within 24 hours post-dose. Despite the high systemic clearance, potent proteasome inhibition was observed in blood and a variety of tissues. Together with rapid and irreversible target binding, the high clearance may provide an advantage in that "unnecessary" exposure to the drug is minimized and potential drug-related side effects may be reduced.
- anticancer agents
- drug clearance
- drug disposition
- drug distribution
- excretion
- extrahepatic drug metabolism
- pharmacokinetics
- Received March 7, 2011.
- Accepted July 12, 2011.
- The American Society for Pharmacology and Experimental Therapeutics