Abstract

Carfilzomib [(2S)-N-[(S)-1-[(S)-4-methyl-1-[(R)-2-methyloxiran-2-yl]-1-oxopentan-2-ylcarbamoyl]-2-phenylethyl]-2-[(S)-2-(2-morpholinoacetamido)-4-phenylbutanamido]-4-methylpentanamide, 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. After intravenous administration, the plasma concentration of carfilzomib declined rapidly in a biphasic manner. Carfilzomib displayed high plasma clearance [195–319 ml/(min · kg)], a short-terminal half-life (5–20 min), and rapid and wide tissue distribution in rats. The exposure to carfilzomib (C_max and area under the curve) increased dose proportionally from 2 to 4 mg/kg but less than dose proportionally from 4 to 8 mg/kg. The high clearance was mediated predominantly 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 approximately 26 and 31% of the total dose, respectively, for a total of 57% within 24 h postdose. 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.