Pazopanib for the treatment of patients with advanced renal cell carcinoma.

Carbone Cancer Center, University of Wisconsin, 7020 Wisconsin Institutes for Medical Research, Madison, WI 53705-2225, USA.
Clinical Medicine Insights: Oncology 01/2010; 4:95-105. DOI: 10.4137/CMO.S4088
Source: PubMed

ABSTRACT Dramatic advances in the care of patients with advanced renal cell carcinoma have occurred over the last ten years, including insights into the molecular pathogenesis of this disease, that have now been translated into paradigm-changing therapeutic strategies. Elucidating the importance of signaling cascades related to angiogenesis is notable among these achievements. Pazopanib is a novel small molecule tyrosine kinase inhibitor that targets VEGFR-1, -2, and -3; PDGFR-α, PDGFR-β; and c-kit tyrosine kinases. This agent exhibits a distinct pharmacokinetic profile as well as toxicity profile compared to other agents in the class of VEGF signaling pathway inhibitors. This review will discuss the scientific rationale for the development of pazopanib, as well as preclinical and clinical trials that led to approval of pazopanib for patients with advanced renal cell carcinoma. The most recent information, including data from 2010 national meeting of the American Society of Clinical Oncology, and the design of ongoing Phase III trials, will be discussed. Finally, an algorithm utilizing Level I evidence for the treatment of patients with this disease will be proposed.

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    ABSTRACT: Introduction As angiogenic pathways have become important targets for inhibition of tumor growth, we examined the concept of dual pathway blockade by small-molecule tyrosine kinase inhibitors targeting vascular endothelial and epidermal growth factor receptors. Methods Escalating doses of pazopanib (400-800 mg once daily [QD]) plus erlotinib (100-150 mg QD) doses were evaluated in cohorts of 3-6 adults with advanced solid tumors. Twelve additional patients were enrolled in an expansion cohort to confirm the maximum tolerated dose (MTD). Results The MTD, defined during assessment of 20 patients, was pazopanib 600 mg plus erlotinib 150 mg. Two dose-limiting toxicities, rash and elevated liver enzymes, occurred at pazopanib 800 mg and erlotinib 150 mg. Overall, 30 % and 27 % of patients required dose interruption of pazopanib or erlotinib, respectively; 15 % of patients required a dose reduction of erlotinib to manage toxicities. The most common adverse events in patients treated with any dose regimen of pazopanib plus erlotinib (N = 33) were diarrhea, rash, nausea, and decreased appetite. The adverse-event profile of the combination did not appear to differ from that of each compound administered alone. Coadministration of pazopanib 600 mg QD and erlotinib 150 mg QD did not consistently affect the pharmacokinetics of either compound relative to that observed for either compound administered alone. Of 26 patients evaluated for efficacy, 3 (12 %; all non-small-cell lung cancer) had partial response and 10 (38 %) had stable disease. Conclusions Concomitant administration of pazopanib 600 mg and erlotinib 150 mg is feasible, with a manageable toxicity profile. These results support further clinical development of the pazopanib-erlotinib combination.
    Investigational New Drugs 11/2012; 31(4). · 3.50 Impact Factor
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    ABSTRACT: Pyrimidine (imatinib, dasatinib, nilotinib and pazopanib), pyridine (sorafenib) and pyrrole (sunitinib) tyrosine kinase inhibitors (TKIs) are multi-targeted TKIs with high activity towards several families of receptor and non-receptor tyrosine kinases involved in angiogenesis, tumour growth and metastatic progression of cancer. These orally administered TKIs have quite diverse characteristics with regard to absorption from the gastrointestinal tract. Absolute bioavailability in humans has been investigated only for imatinib (almost 100%) and pazopanib (14-39%; n = 3). On the basis of human radioactivity data, dasatinib is considered to be well absorbed after oral administration (19% and 0.1% of the total radioactivity were excreted as unchanged dasatinib in the faeces and urine, respectively). Quite low absolute bioavailability under fasted conditions is assumed for nilotinib (31%), sorafenib (50%) and sunitinib (50%). Imatinib, dasatinib and sunitinib exhibit dose-proportional increases in their area under the plasma concentration-time curve values over their therapeutic dose ranges. Less than dose-proportional increases were observed for nilotinib at doses ≥400 mg/day and for sorafenib and pazopanib at doses ≥800 mg/day. At steady state, the accumulation ratios are 1.5-2.5 (unchanged imatinib), 2.0 (nilotinib once-daily dosing), 3.4 (nilotinib twice-daily dosing), 1.2-4.5 (pazopanib), 5.7-6.4 (sorafenib) and 3.0-4.5 (sunitinib). Concomitant intake of a high-fat meal does not alter exposure to imatinib, dasatinib and sunitinib but leads to considerably increased bioavailability of nilotinib and pazopanib and decreased bioavailability of sorafenib. With the exception of pazopanib, the TKIs described here have large apparent volumes of distribution, exceeding the volume of body water by at least 4-fold.Very low penetration into the central nervous system in humans has been reported for imatinib and dasatinib, but there are currently no published human data for nilotinib, pazopanib, sorafenib or sunitinib. All TKIs that have been described are more than 90% bound to the plasma proteins: α1-acid glycoprotein and/or albumin. They are metabolized primarily via cytochrome P450 (CYP) 3A4, the only exception being sorafenib, for which uridine diphosphate glucuronosyltransferase 1A9 is the other main enzyme involved. Active metabolites of imatinib and sunitinib contribute to their antitumour activity. Although some patient demographics have been identified as significant co-factors that partly explain interindividual variability in exposure to TKIs, these findings have not been regarded as sufficient to recommend age-, sex-, bodyweight- or ethnicity-specific dose adjustment. Systemic exposure to imatinib, sorafenib and pazopanib increases in patients with hepatic impairment, and reduction of the initial therapeutic dose is recommended in this subpopulation. The starting dose of imatinib should also be reduced in renally impaired subjects. Because the solubility of dasatinib is pH dependent, co-administration of histamine H2-receptor antagonists and proton pump inhibitors with dasatinib should be avoided. With the exception of sorafenib, systemic exposure to TKIs is significantly decreased/increased by co-administration of potent CYP3A4 inducers/inhibitors, and so it is strongly recommended that the TKI dose is adjusted or that such co-administration is avoided. Caution is also recommended for co-administration of CYP3A4 substrates with TKIs, especially for those with a narrow therapeutic index. However, current recommendations with regard to dose adjustment of TKIs need to be validated in clinical studies. Further investigations are needed to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess theclinical relevance of their interaction potential and inhibitory effects on metabolizing enzymes and transporters.
    Clinical Pharmacokinetics 08/2011; 50(9):551-603. · 5.49 Impact Factor
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    ABSTRACT: Advances in our understanding of renal cancer biology have led to a new treatment paradigm in renal cancer. Tyrosine kinase inhibitors (TKI), that target the intracellular kinase domain of the VEGF receptor, have become established as the most successful class of agent in this disease. Three TKIs are currently approved for use in patients with advanced disease. Newer, more potent inhibitors have reached phase III clinical testing, meaning others are likely to follow. In 2009, pazopanib became the most recent TKI to receive FDA approval. This review sets out to discuss the key opportunities and challenges associated with TKI use in RCC, focusing particularly on pazopanib. We also review the current place of pazopanib in the management of patients with advanced disease, in what is a rapidly evolving therapeutic landscape.
    Clinical Medicine Insights: Oncology 01/2011; 5:333-42.

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