Pharmacokinetics, Pharmacodynamics, Metabolism, Distribution, and Excretion of Carfilzomib in Rats

Jiao, Yang; Wang, Zhengping; Fang, Yifeng; Jiang, Jing; Zhao, Frances; Wong, Hansen; Bennett, Mark K.; Molineaux, Christopher J.; Kirk, Christopher J.

doi:10.1124/dmd.111.039164

Cited by 115 publications

(124 citation statements)

References 30 publications

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“…However, there was a significant correlation between inhibition of CT‐L activity and ProCISE in whole blood and PBMCs for the aggregate of paired samples (Table SII). Inhibition levels were also equivalent in patients with MM receiving 20 mg/m 2 carfilzomib as a 2‐ to 10‐min or 30‐min infusion, which is consistent with results reported in animals (Yang et al , 2011). It is noteworthy that the overall level of CT‐L inhibition seen with carfilzomib is higher than the 65–70% inhibition rate reported in bortezomib‐treated patients (Orlowski et al , 2002; Papandreou et al , 2004; Moreau et al , 2008).…”

Section: Discussionsupporting

confidence: 89%

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

et al. 2016

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SummaryWhile proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme‐linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15–56 mg/m2), dose‐dependent inhibition of c20S and i20S chymotrypsin‐like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow–derived CD138+ tumour cells. Carfilzomib‐induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near‐complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.

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Section: Discussionsupporting

confidence: 89%

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

et al. 2016

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“…However, despite the excellent efficacy observed in preclinical models of solid cancer (Yang et al, 2006;Demo et al, 2007;Ao et al, 2012), CFZ demonstrated disappointing results clinically when tested in patients with advanced solid tumors . Although the exact mechanisms underlying the discrepancies between the preclinical and clinical observations are currently unknown, one potential explanation is the rapid metabolic degradation of CFZ in vivo (Yang et al, 2011). CFZ degradation in humans is mainly due to peptide cleavage and epoxide ring opening, resulting in plasma half-life of less than 30 minutes .…”

Section: Introductionmentioning

confidence: 99%

Polymer Micelle Formulations of Proteasome Inhibitor Carfilzomib for Improved Metabolic Stability and Anticancer Efficacy in Human Multiple Myeloma and Lung Cancer Cell Lines

Reichel

et al. 2015

J Pharmacol Exp Ther

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Carfilzomib (CFZ) is a second-generation proteasome inhibitor drug approved for the treatment of multiple myeloma. Contrary to its excellent antimyeloma activity, CFZ has shown only limited efficacy in patients with solid malignancies. This lack of efficacy has been attributed in part to rapid degradation of CFZ in the body, possibly hindering the ability of CFZ to access the proteasome target in solid tumors. We hypothesized that polymer micelles, a currently Food and Drug Administration-approved nanoparticle drug delivery formulation, may protect CFZ from metabolic degradation and thus expand the clinical utility of the drug as an anticancer agent. To test our hypothesis, we prepared CFZ-entrapped polymer micelle particles with various compositions and drug release profiles and examined the extent of the CFZ metabolism in vitro using mouse liver homogenates. We also assessed the cytotoxic activities of the CFZ-entrapped micelle formulations in human cancer cell lines derived from B lymphocytes (RPMI-8226) and the lung (H460). Our data indicated that polymer micelle-based formulations can improve metabolic stability and cytotoxic effects of CFZ compared with free CFZ in human cancer cell lines tested. Taken together, these results suggest that polymer micelles may have potential as a delivery system for CFZ with an extended therapeutic utility for nonhematologic malignancies in the future.

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“…Preclinical studies in rats and monkeys have shown that carfilzomib is rapidly and extensively distributed and potently inhibits proteasome activity in a variety of tissues after i.v. administration (Yang et al, 2011). Carfilzomib has a systemic clearance (CL) greater than hepatic blood flow and a terminal half-life (t 1/2 ) shorter than 30 minutes.…”

Section: Introductionmentioning

confidence: 99%

Clinical Pharmacokinetics, Metabolism, and Drug-Drug Interaction of Carfilzomib

Wang¹,

Jiao²,

Kirk³

et al. 2012

Drug Metab Dispos

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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.

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Pharmacokinetics, Pharmacodynamics, Metabolism, Distribution, and Excretion of Carfilzomib in Rats

Abstract: Carfilzomib [(2S)-N-[(S)-1-[(S)-4-methyl-1-[(R)-2-methyloxiran-2-yl]-1-oxopentan-2-ylcarbamoyl]-2-phenylethyl]-2-[(S)-

Cited by 115 publications

References 30 publications

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

Polymer Micelle Formulations of Proteasome Inhibitor Carfilzomib for Improved Metabolic Stability and Anticancer Efficacy in Human Multiple Myeloma and Lung Cancer Cell Lines

Clinical Pharmacokinetics, Metabolism, and Drug-Drug Interaction of Carfilzomib

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