Vemurafenib (PLX4032): An Orally Available Inhibitor of Mutated BRAF for the Treatment of Metastatic Melanoma

Heakal, Yasser; Kester, Mark; Savage, Scott W.

doi:10.1345/aph.1q363

Cited by 46 publications

(36 citation statements)

References 36 publications

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“…In the past 40 years, patients with advanced metastatic melanoma have had very few treatment options, with no first-line standard of care that offered a proven overall survival benefit (Eggermont et al, 2011;Heakal et al, 2011). The prognosis for these patients has been very poor, with a median survival time of 6-9 months and a 3-year survival rate of only 10% to 15% (Eggermont et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, advances have been made in the development of targeted therapies that kill melanoma cells or therapies that specifically target mutated proteins in cell signaling pathways. One pathway that has been established in mediating growth signals that drive cancer is the RAS-RAF-MEK-ERK mitogen-activated protein (MAP) kinase cascade (Roberts and Der, 2007;Heakal et al, 2011). Three genes encode the RAF-serine/ threonine kinases, one of which is b-raf.…”

Section: Introductionmentioning

confidence: 99%

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The Metabolic Drug-Drug Interaction Profile of Dabrafenib: In Vitro Investigations and Quantitative Extrapolation of the P450-Mediated DDI Risk

et al. 2014

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Dabrafenib is a potent ATP-competitive inhibitor for the V600 mutant b-rapidly accelerated fibrosarcoma (b-raf) kinase currently approved in the United States for the treatment of metastatic melanoma. Studies were conducted in human liver microsomes, recombinant human cytochrome P450 (P450) enzymes, and human hepatocytes to investigate the potential of dabrafenib and its major circulating metabolites to perpetrate pharmacokinetic drug-drug interactions (DDIs) as well as have their own pharmacokinetics affected (victim) by coadministered drugs. Dabrafenib metabolism was mediated by CYP2C8 (56% to 67%) and CYP3A4 (24%); in addition, it has demonstrated inhibition of CYP2C8, 2C9, 2C19, 3A4 (atorvastatin), and (nifedipine), with calculated IC 50 values of 8.2, 7.2, 22.4, 16, and 32 mM. It also demonstrated metabolism-dependent inhibition of CYP3A4 with a maximal inactivation rate constant of 0.040 minute 21 and a concentration required to achieve half-maximal inactivation for CYP3A4 of 38 mM. Hydroxy-dabrafenib inhibited CYP1A2, 2C9, and 3A4 (midazolam) with calculated IC 50 values of 83, 29, and 44 mM, and carboxy-dabrafenib did not inhibit any of the P450 enzymes tested. Desmethyl-dabrafenib inhibited CYP2B6, 2C8, 2C9, 2C19, and 3A4 (midazolam, atorvastatin, and nifedipine) with calculated IC 50 values of 78, 47, 6.3, 36, 17, 20, and 28 mM, respectively. At 30 mM dabrafenib showed increases in CYP2B6 and CYP3A4 mRNA expression indicative of induction. The potential clinical relevance of these findings was explored by using mechanistic static mathematical models to estimate the magnitude of change (area under the curve change) as a result of P450-mediated DDI interactions. This risk-assessment approach indicated that dabrafenib is unlikely to perpetrate any in vivo DDIs by inhibition mechanisms, but is a likely inducer of CYP3A4 and a victim of CYP3A4 and CYP2C8 inhibitors. Furthermore, inclusion of the in vitro drug interaction data for dabrafenib metabolites did not impact the overall clinical risk assessment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Metabolic Drug-Drug Interaction Profile of Dabrafenib: In Vitro Investigations and Quantitative Extrapolation of the P450-Mediated DDI Risk

et al. 2014

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“…B-Raf acts as catalyst for the phosphorylation of serine and threonine residues on target proteins in the RAS/ RAF/MEK/ERK/MAP Kinase signaling pathway which directs cell growth, survival, differentiation, and secretion. Mutations in BRAF result in tumor growth by causing constitutive signaling in this pathway and subsequent deregulation of the processes it sub serves [8,9]. While most notably associated with malignant melanoma, acquired mutations in BRAF have also been found in non-hodgkins lymphoma, colorectal cancer, and Adenocarcinoma of the lung [10].…”

Section: Discussionmentioning

confidence: 99%

Dabrafenib Resistance Overridden by Switch to Vemurafenib and Trametinib in 53-year Old Patient with Metastatic Lung Carcinoma: Clinical Case Report

Gaynor¹

2015

JCPCR

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Introduction: A small subset of patients with Adeno-carcinoma of the lung harbor mutations in BRAF, a proto-oncogene involved in cell signaling. Acquired resistance to BRAF inhibition has been reported in nearly half of patients with metastatic melanoma who are treated with BRAF inhibitors. Resistance to BRAF inhibition has been ameliorated by co-targeting additional sites in the RAS/RAF/ MEK pathway.

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“…Vemurafenib produced improved OS and PFS rates in patients. Thus, it offers a novel, first-line, personalized treatment for patients with mutated BRAF [38]. …”

Section: Vemurafenibmentioning

confidence: 99%

Targeted Agents for the Treatment of Melanoma: An Overview

Tseng¹,

Li²,

Hsieh+³

2013

Recent Advances in the Biology, Therapy and Management of Melanoma

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Vemurafenib (PLX4032): An Orally Available Inhibitor of Mutated BRAF for the Treatment of Metastatic Melanoma

Abstract: Vemurafenib offers a novel, first-line, personalized therapy for patients who have mutated BRAF. Clinical trials of vemurafenib in combination with ipilimumab or other targeted or cytotoxic chemotherapeutic agents may provide more effective regimens with long-term clinical benefit.

Cited by 46 publications

References 36 publications

The Metabolic Drug-Drug Interaction Profile of Dabrafenib: In Vitro Investigations and Quantitative Extrapolation of the P450-Mediated DDI Risk

The Metabolic Drug-Drug Interaction Profile of Dabrafenib: In Vitro Investigations and Quantitative Extrapolation of the P450-Mediated DDI Risk

Dabrafenib Resistance Overridden by Switch to Vemurafenib and Trametinib in 53-year Old Patient with Metastatic Lung Carcinoma: Clinical Case Report

Targeted Agents for the Treatment of Melanoma: An Overview

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