title: Clinical pharmacokinetics, metabolism, and drug-drug interaction of carfilzomib.
abstract: Carfilzomib, an irreversible proteasome inhibitor, has a favorable safety profile and significant antitumor 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 minutes, 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 CYP3A activity. Plasma concentrations of carfilzomib declined rapidly and in a biphasic manner after intravenous administration. The systemic half-life was short and the systemic clearance rate was higher than hepatic blood flow. Carfilzomib was cleared largely extrahepatically via peptidase cleavage and epoxide hydrolysis. Cytochrome P450-mediated metabolism played a minor role, suggesting that coadministration of P450 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 rapid systemic clearance and short half-life of carfilzomib limit clinically significant DDI.
authors.affiliation: Onyx Pharmaceuticals, 249 E. Grand Ave., South San Francisco, CA 94080, USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Wang
authors.forename: Jinfu
authors.initials: J
authors.lastname: Yang
authors.forename: Christopher
authors.initials: C
authors.lastname: Kirk
authors.forename: Ying
authors.initials: Y
authors.lastname: Fang
authors.forename: Melissa
authors.initials: M
authors.lastname: Alsina
authors.forename: Ashraf
authors.initials: A
authors.lastname: Badros
authors.forename: Kyriakos
authors.initials: K
authors.lastname: Papadopoulos
authors.forename: Alvin
authors.initials: A
authors.lastname: Wong
authors.forename: Tina
authors.initials: T
authors.lastname: Woo
authors.forename: Darrin
authors.initials: D
authors.lastname: Bomba
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002853:Chromatography, Liquid; D004347:Drug Interactions; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib