Effect of the CYP3A inhibitor ketoconazole on the pharmacokinetics and pharmacodynamics of bortezomib in patients with advanced solid tumors: A prospective, multicenter, open-label, randomized, two-way crossover drug—drug interaction study

Venkatakrishnan, Karthik; Rader, Michael; Ramanathan, Ramesh K.; Ramalingam, Suresh S.; Chen, Eric X.; Riordan, William; Trepicchio, William L.; Cooper, Michael R.; Karol, Michael D.; Moltke, Lisa von; Neuwirth, Rachel; Egorin, Merrill J.; Chatta, Gurkamal S.

doi:10.1016/j.clinthera.2009.11.012

Cited by 56 publications

(41 citation statements)

References 38 publications

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“…The results from these metabolic studies suggest that carfilzomib can be coadministered with P450 inhibitors or inducers without altering its PK profile. In contrast, potent CYP3A inhibitors and inducers are known to have significant effects on the exposure of bortezomib in patients (Venkatakrishnan et al, 2009;Hellmann et al, 2011); consequently, coadministration is not recommended.…”

Section: Discussionmentioning

confidence: 99%

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

Wang¹,

Jiao²,

Kirk³

et al. 2012

Drug Metab Dispos

125

128

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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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Section: Discussionmentioning

confidence: 99%

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

Wang¹,

Jiao²,

Kirk³

et al. 2012

Drug Metab Dispos

125

128

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“…Despite the encouraging clinical success of bortezomib, adverse effects including painful peripheral neuropathy have been reported, and a significant fraction of patients relapse from or are refractory to treatment with bortezomib (Orlowski et al, 2002(Orlowski et al, , 2007aRichardson et al, 2003Richardson et al, , 2005Goy et al, 2005;O'Connor et al, 2005). In addition, bortezomib is metabolized primarily by cytochrome P450 3A4 (Uttamsingh et al, 2005), and coadministration of cytochrome P450 3A4 inhibitors such as ketoconazole causes a significant change in bortezomib plasma levels in humans (Venkatakrishnan et al, 2009). In the past several years, the next generation of proteasome inhibitors has been explored, with the aim to improve safety and efficacy profiles.…”

Section: Introductionmentioning

confidence: 99%

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

Jiao¹,

Wang²,

Fang³

et al. 2011

Drug Metab Dispos

116

111

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“…Moreover, extensive clinical drug-drug inter action studies have not been performed, except for two studies on the coadministration of bortezomib with ketoconazole [49] or omeprazole [50], which are able to weakly affect Drug Evaluation Romano, Conticello & Di Raimondo or not affect bortezomib metabolism, respectively. Recently, it has been reported that the proteasome-inhibitory and anticancer activity of bortezomib can be blocked by green tea polyphenols, quercetin, myricetin and ascorbic acid through their interaction with the structure of a boronic acid to form boronic ester complexes [51].…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 98%

Bortezomib for the Treatment of Previously Untreated Multiple Myeloma

2013

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Management of multiple myeloma (MM) has been drastically changed in the last 10 years thanks to the introduction of novel agents, which, combined with the backbone of classical chemotherapy, have led to a significant improvement in disease control. Bortezomib is the first reversible proteasome inhibitor approved for the treatment of MM, with wide synergism in vitro and in vivo with a plethora of drugs active for MM. In patients eligible for autologous stem cell transplantation (ASCT), the achievement of complete response or very good partial response before ASCT is associated with prolonged progression-free and overall survival. Thus, the goal of induction regimens should include, at least for younger patients, a continued improvement of the quality and depth of the achieved response. This article is focused on reviewing the major efforts in frontline therapy for MM, including bortezomib-containing induction regimens in patients either eligible or ineligible for ASCT.

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Effect of the CYP3A inhibitor ketoconazole on the pharmacokinetics and pharmacodynamics of bortezomib in patients with advanced solid tumors: A prospective, multicenter, open-label, randomized, two-way crossover drug—drug interaction study

Cited by 56 publications

References 38 publications

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

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

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

Bortezomib for the Treatment of Previously Untreated Multiple Myeloma

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