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Clinical Pharmacokinetics Sep 2017Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell... (Review)
Review
Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies.
Topics: Angiogenesis Inhibitors; Animals; Dose-Response Relationship, Drug; Humans; Indazoles; Neoplasms; Pyrimidines; Randomized Controlled Trials as Topic; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sulfonamides
PubMed: 28185218
DOI: 10.1007/s40262-017-0510-z -
Drugs Jul 2014Pazopanib (Votrient(®)) is an orally administered multi-tyrosine kinase inhibitor that is approved in the EU, the US and other countries for the treatment of advanced... (Review)
Review
Pazopanib (Votrient(®)) is an orally administered multi-tyrosine kinase inhibitor that is approved in the EU, the US and other countries for the treatment of advanced renal cell carcinoma. Pazopanib predominantly inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β, and the stem cell factor receptor c-Kit, resulting in inhibition of tumour angiogenesis, cell growth and survival. In randomized controlled trials in patients with advanced, predominantly clear-cell, renal cell carcinoma, progression-free survival (PFS) and the objective response rate were significantly greater in pazopanib recipients than in placebo recipients (VEG105192 trial), and pazopanib was noninferior to sunitinib with respect to PFS (COMPARZ study). In a patient-preference, crossover study involving 10 weeks of treatment with each drug (PISCES study), significantly more patients expressed a preference for pazopanib than for sunitinib, with their preference being based primarily on tolerability and quality-of-life issues. Health-related quality-of-life (HR-QOL) assessments generally favoured pazopanib over sunitinib in COMPARZ, and pazopanib did not cause deterioration in HR-QOL compared with placebo in VEG105192. Pazopanib caused less myelosuppression, hand-foot syndrome, mucositis/stomatitis, dysgeusia and fatigue than sunitinib, but more abnormal liver function tests. Therefore, pazopanib was noninferior to sunitinib with respect to efficacy in the treatment of advanced renal cell carcinoma, but had a differentiated tolerability profile, which affected HR-QOL and patient preference.
Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Proliferation; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Quality of Life; Sulfonamides
PubMed: 24935162
DOI: 10.1007/s40265-014-0243-3 -
Critical Reviews in Oncology/hematology Mar 2011Pazopanib is an oral, multi-targeted, tyrosine kinase inhibitor (TKI) that binds to the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth... (Review)
Review
Pazopanib is an oral, multi-targeted, tyrosine kinase inhibitor (TKI) that binds to the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and several other key proteins responsible for angiogenesis, tumor growth and cell survival. Pazopanib exhibited in vivo and in vitro activity against tumor growth and, in early clinical trials, was well tolerated with the main side effects being hypertension, fatigue and gastrointestinal disorders. Pazopanib showed clinical activity in several tumors including renal cell cancer (RCC), breast cancer, soft tissue sarcoma, thyroid cancer, hepatocellular cancer and cervical cancer. A phase III clinical trial in metastatic RCC patients showed a significant improvement in progression-free survival, leading to its approval in the US. In metastatic breast cancer, the combination of pazopanib with lapatinib was more effective than lapatinib alone. At the time of the current publication, pazopanib is being evaluated in more than 35 phase II and III trials.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Indazoles; Neoplasms; Pyrimidines; Sulfonamides
PubMed: 20456972
DOI: 10.1016/j.critrevonc.2010.02.012 -
Food and Chemical Toxicology : An... Nov 2023Parkinson's disease (PD) is characterized by motor impairments and progressive dopaminergic neuronal death in the substantia nigra (SN). Recently, the involvement of...
Parkinson's disease (PD) is characterized by motor impairments and progressive dopaminergic neuronal death in the substantia nigra (SN). Recently, the involvement of other regulated cell death (RCD) machineries has been highlighted in PD. Necroptosis is controlled by p-RIPK1, p-RIPK3, and p-MLKL and negatively regulated by caspase-8. Ferroptosis is characterized by iron overload and accumulation of reactive oxygen species. Interestingly, the molecular chaperone complex HSP90/CDC37 has been reported to directly regulate necroptosis, ferroptosis, and some PD-associated proteins. We investigated the potential anti-necroptotic and anti-ferroptotic effects of the anti-cancer drug pazopanib, uncovering the HSP90/CDC37 complex as a master RCD modulator in rotenone-induced Parkinsonism in rats. Oral administration of 15 mg/kg pazopanib to rotenone-intoxicated rats for three weeks improved motor deficits, debilitated histopathological changes, and increased striatal dopaminergic levels. Pazopanib suppressed LRRK2 and c-Abl. Pazopanib displayed an anti-necroptotic effect through inhibition of the p-RIPK1/p-RIPK3/p-MLKL pathway and activation of caspase-8. Moreover, pazopanib inhibited the ferroptotic p-VEGFR2-PKCβII-PLC-γ-ACSL-4 pathway, iron, 4-HNE, and PTGS2 while increasing GPX-4 and GSH levels. Taken together, the current research sheds light on the repositioning of pazopanib targeting HSP90/CDC37 and its multiple RCD mechanisms, which would offer a new perspective for therapeutic strategies in PD.
Topics: Rats; Animals; Rotenone; Caspase 8; Parkinsonian Disorders; Parkinson Disease; Dopamine; Ferroptosis; Molecular Chaperones; HSP90 Heat-Shock Proteins
PubMed: 37820786
DOI: 10.1016/j.fct.2023.114069 -
Expert Opinion on Pharmacotherapy May 2013Pazopanib (GW786034, Votrient®) is a vascular endothelial growth factor receptor-focused multi-tyrosine kinase inhibitor involved in inhibiting the angiogenesis... (Review)
Review
INTRODUCTION
Pazopanib (GW786034, Votrient®) is a vascular endothelial growth factor receptor-focused multi-tyrosine kinase inhibitor involved in inhibiting the angiogenesis pathway. The agent was recently registered for use in soft tissue sarcomas, a group of diseases with a major unmet medical need.
AREAS COVERED
The relevance of angiogenesis in soft tissue sarcomas is discussed. These data were the basis to decide on the development of pazopanib in these diseases. The clinical pharmacology of pazopanib, as far as practically relevant, is summarized. After the first observations of possible activity in soft tissue sarcomas in the Phase I study, a Phase II and subsequent randomized placebo-controlled Phase III study were performed and are being put into perspective in this review.
EXPERT OPINION
Pazopanib is an active drug for the treatment of chemotherapy-failing nonadipocytic soft tissue sarcomas. It almost triples progression-free survival significantly from 1.6 to 4.6 months in this heavily pretreated population. The safety profile is manageable, exemplified by the high dose intensity that can be achieved over time. Pazopanib can be considered as part of the standard of care for patients with soft tissue sarcomas.
Topics: Angiogenesis Inhibitors; Clinical Trials as Topic; Disease-Free Survival; Humans; Indazoles; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Sulfonamides
PubMed: 23488774
DOI: 10.1517/14656566.2013.780030 -
Expert Review of Anticancer Therapy Jun 2012Patients with advanced metastatic soft tissue sarcoma (STS) have a poor prognosis, and in the last two decades of the 20th century their overall survival has remained... (Review)
Review
Patients with advanced metastatic soft tissue sarcoma (STS) have a poor prognosis, and in the last two decades of the 20th century their overall survival has remained unchanged. Improved treatments are needed for these patients and for preventing metastases in earlier stages of disease. Numerous novel agents and new combination regimens are undergoing clinical testing in STS. Some of these agents show promising activity. Pazopanib is one such agent that has undergone Phase II and III evaluations in advanced STS. Pazopanib is a multi-tyrosine kinase inhibitor, blocking various signaling pathways, thereby preventing angiogenesis and metastasis, and inhibiting tumor cell growth and survival. In a Phase II study, pazopanib demonstrated activity in patients with advanced leiomyosarcomas, synovial sarcomas and other eligible STSs. This activity was confirmed in a Phase III trial, where pazopanib significantly extended the median progression-free survival versus placebo in a variety of STS subtypes.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Humans; Indazoles; Protein Kinase Inhibitors; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sulfonamides
PubMed: 22716487
DOI: 10.1586/era.12.41 -
Current Opinion in Investigational... Dec 2008Pazopanib, which is being developed by GlaxoSmithKline plc, is an oral, second-generation multi-targeted tyrosine kinase inhibitor that targets VEGFR, platelet-derived... (Review)
Review
Pazopanib, which is being developed by GlaxoSmithKline plc, is an oral, second-generation multi-targeted tyrosine kinase inhibitor that targets VEGFR, platelet-derived growth factor receptor and c-kit, key proteins responsible for tumor growth and survival. Pazopanib exhibited good potency against all of the human VEGFRs and closely related tyrosine receptor kinases in vitro, and demonstrated antitumor activity in several human tumor xenografts, including renal cell carcinoma (RCC), and breast and lung cancer. In phase I and II clinical trials, pazopanib was generally well tolerated with the main side effects being hypertension, fatigue or gastrointestinal disorders. Pazopanib alone caused a decrease in tumor size and stable disease in a significant number of patients, including those with RCC, NSCLC and gynecological tumors. The combination of pazopanib with lapatinib was effective in patients with breast cancer. At the time of publication, pazopanib monotherapy was being evaluated in phase III trials in patients with RCC and as combination therapy with lapatinib in patients with breast cancer. In addition, phase I and II trials were being conducted to assess pazopanib alone or in combination with a range of chemotherapeutics in patients with solid tumors or multiple myeloma.
Topics: Animals; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Drugs, Investigational; Humans; Indazoles; Neoplasms; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sulfonamides
PubMed: 19037839
DOI: No ID Found -
The Annals of Pharmacotherapy Jun 2010To summarize the currently available clinical data on pazopanib, as well as review the merits and adverse effects of pazopanib in the treatment of renal cell carcinoma... (Review)
Review
OBJECTIVE
To summarize the currently available clinical data on pazopanib, as well as review the merits and adverse effects of pazopanib in the treatment of renal cell carcinoma (RCC).
DATA SOURCES
A literature search was performed of MEDLINE, PubMed, and the American Society of Clinical Oncology abstracts from January 1995 to February 2010, using the primary search terms pazopanib, GW786034, Votrient, and tyrosine kinase inhibitors.
STUDY SELECTION AND DATA EXTRACTION
All available English-language articles and trials that described the pharmacokinetics, pharmacology, pharmacodynamics, clinical activity, or adverse effects of pazopanib were reviewed.
DATA SYNTHESIS
Pazopanib is a second-generation multitargeted tyrosine kinase inhibitor (TKI) that has exhibited antiangiogenic and antitumor activity. Phase 1 clinical trials have established the safety and tolerability of pazopanib 800 mg orally daily. Phase 2 and 3 studies have shown promising activity in RCC, including treatment naïve or cytokine-pretreated patients, demonstrating a greater rate of total disease control with pazopanib compared to placebo. Activity has also been shown in a variety of other cancers, including ovarian cancer, non-small-cell lung cancer, breast cancer, and soft tissue sarcoma. The most common adverse effects of pazopanib include nausea, diarrhea, hypertension, hair depigmentation, and elevated transaminase levels. Adverse effects are most commonly Grades 1-2. Other Phase 3 trials are ongoing in RCC, including a comparison to sunitinib, another TKI used in RCC, as well as trials in other tumor types.
CONCLUSIONS
Current data suggest pazopanib to be a viable treatment option as first-line therapy for advanced RCC. Data are awaited comparing pazopanib to other TKIs. Until results of head-to-head trials conducted of the various agents are available, it cannot be said whether pazopanib is more tolerable or efficacious than currently available therapies.
Topics: Administration, Oral; Animals; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Delivery Systems; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides
PubMed: 20407031
DOI: 10.1345/aph.1M251 -
Drugs Mar 2011Treatment options for renal cell carcinoma (RCC) have multiplied in the past 5 years. Pazopanib is the third tyrosine kinase inhibitor (TKI) and the sixth targeted... (Review)
Review
Treatment options for renal cell carcinoma (RCC) have multiplied in the past 5 years. Pazopanib is the third tyrosine kinase inhibitor (TKI) and the sixth targeted therapy that has received US FDA approval for the treatment of advanced or metastatic RCC. The primary mechanism of action of pazopanib in RCC is through its antiangiogenic properties via inhibition of the intracellular tyrosine kinase of vascular endothelial growth factor receptor and platelet-derived growth factor receptor. A placebo-controlled phase III study demonstrated that pazopanib significantly improved response rates and progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients. Among treatment-naïve patients, the response rate was 32% and PFS was 11.1 months. In cytokine-pretreated patients, the response rate and PFS were 29% and 7.4 months, respectively. Common adverse effects of pazopanib include diarrhoea, hypertension and elevation of liver enzymes. Overall, the adverse effect profile of pazopanib is similar to that of other TKIs used for the treatment of RCC, but variation in the incidence and severity may exist. Pazopanib has an increased propensity to cause hepatotoxicity, which may be fatal in rare cases. Hepatic function must be monitored closely with dose interruption and/or reduction if elevation of hepatic function tests occurs. Pazopanib is administered on an empty stomach at a dose of 800 mg daily until disease progression, but dose reduction may be required in patients with baseline elevation of hepatic function tests, particularly total bilirubin. The minimum dose recommended for baseline hepatic dysfunction or toxicity is 200 mg daily. The potential for drug interactions exists for pazopanib. It is a substrate of cytochrome P450 (CYP) 3A4, P-glycoprotein and breast cancer resistance protein, and it weakly inhibits CYP3A4, CYP2C8 and CYP2D6, and potently inhibits UGT1A1 and OATP1B1. Currently, no study has directly compared pazopanib with other first- or second-line therapies in RCC. However, published clinical trials of pazopanib show similar efficacy outcomes to those of other targeted therapies. Therefore, pazopanib may be considered a first-line treatment option among other therapies including sunitinib, temsirolimus, and bevacizumab plus interferon-α. After failure of cytokine therapy, pazopanib is a treatment option as well as sorafenib or bevacizumab. No study has evaluated pazopanib treatment after failure of another targeted therapy. Future studies will further clarify the comparative efficacy of pazopanib with other agents as well as optimal sequencing with other agents. If similar efficacy is seen among the TKIs, it is likely that varying incidences of adverse effects may be analysed to tailor therapy according to the patient's individual co-morbidities and preferences.
Topics: Animals; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Controlled Clinical Trials as Topic; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Treatment Outcome
PubMed: 21395357
DOI: 10.2165/11588960-000000000-00000 -
Current Oncology Reports Mar 2007Pazopanib (GW786034) is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived... (Review)
Review
Pazopanib (GW786034) is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and c-kit. Preclinical evaluation has revealed excellent antiangiogenic and antitumor activity, and synergism was observed in combination with chemotherapeutic drugs. Significant antitumor activity was found in animal models of a variety of tumors, accompanied by desirable pharmacokinetics and oral bioavailability. Phase I clinical trials have revealed manageable toxicities and desirable pharmacokinetics as well as activity in renal cancer and several other tumors. Ongoing trials are further evaluating pazopanib in a variety of malignancies.
Topics: Animals; Antineoplastic Agents; Humans; Indazoles; Neoplasms; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides
PubMed: 17288876
DOI: 10.1007/s11912-007-0007-2