Votrient

Pazopanib hydrochloride (PAZ) displays strong intermolecular interaction in its crystal lattice structure, limiting its solubility and dissolution. The development of lipid-based formulations (LbFs) resulted in reduced PAZ loading due to solid-state mediated low liposolubility. This study aims to enhance our understanding of PAZ crystallinity by synthesizing a lipophilic salt and phospholipid complex and investigating its impact on the drug loading in LbFs. The synthesized pazopanib lipophilic salt and phospholipid complex were extensively characterized...

Osteoarthritis (OA) is characterized by cartilage damage, inflammation, and pain. Vascular endothelial growth factor receptors (VEGFRs) have been associated with OA severity, suggesting that inhibitors targeting these receptors alleviate pain (via VEGFR1) or cartilage degeneration (via VEGFR2). We have developed a nanoparticle-based formulation of pazopanib (Votrient), an FDA-approved anticancer drug that targets both VEGFR1 and VEGFR2 (Nano-PAZII). We demonstrate that a single intraarticular injection of Nano-PAZII can effectively reduce joint pain for a prolonged time without substantial side effects in two different preclinical OA rodent models involving either surgical (upon partial medial meniscectomy) or nonsurgical induction (with monoiodoacetate)...

Τhe in vitro biorelevant gastrointestinal transfer (BioGIT) system is a useful screening tool for assessing the impact of dose and/or formulation on early exposure after administration of immediate release or enabling drug products with a glass of water in the fasted state. The objective of this study was to investigate potential limitations. BioGIT experiments were performed with five low solubility active pharmaceutical ingredients with weakly alkaline characteristics: mebendazole (tablet and chewable tablet), Compound E (aqueous solutions, three doses), pazopanib-HCl (Votrient™ tablet, crushed Votrient™ tablet and aqueous suspension), Compound B-diHCl (hard gelatin capsule, three doses) and Compound C (hard gelatin capsule containing nanosized drug and hard gelatin capsule containing micronized drug)...

We aimed to evaluate the efficacy and toxicity of paclitaxel combined with pazopanib in advanced angiosarcoma (AS). The primary end point was progression-free survival (PFS) rate at six months (PFSR6). Planned accrual was 44 patients in order to detect a PFSR6 of >55%, with an interim futility analysis of the first 14 patients. The study did not meet its predetermined interim target of 6/14 patients progression-free at 6 months. At the time of this finding, 26 patients had been enrolled between July 2014 and April 2016, resulting in an overrunning of 12 patients...

Pazopanib (trade name Votrient®) is a potent and selective multi-targeted tyrosine kinase inhibitor that blocks tumor growth and inhibits angiogenesis. Based on a recently reported procedure, we herein report the first synthesis of four potential process impurities generated in the production of pazopanib. The structure of these impurities were synthesized and characterized by 1H NMR, 13C NMR and HRMS data. The possible formation mechanisms of these impurities were also elucidated. These findings should be useful for the quality control of pazopanib in manufacture...

Pazopanib (Votrient) is an orally administered tyrosine kinase inhibitor that blocks VEGF receptors potentially serving as anti-angiogenic treatment for hereditary hemorrhagic telangiectasia (HHT). We report a prospective, multi-center, open-label, dose-escalating study [50 mg, 100 mg, 200 mg, and 400 mg], designed as a proof-of-concept study to demonstrate efficacy of pazopanib on HHT-related bleeding, and to measure safety. Patients, recruited at 5 HHT Centers, required ≥ 2 Curacao criteria AND [anemia OR severe epistaxis with iron deficiency]...

Pazopanib (Votrient®) is an oral small-molecule multi-kinase inhibitor that primarily inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet endothelial growth factor receptor-α, and -β, and the stem-cell factor receptor c-kit. In preliminary experiments using angiogenesis models with mice and rabbits, pazopanib inhibited angiogenesis caused by combined vascular endothelial growth factor and basic fibroblast growth factor. Although pazopanib was developed as a therapeutic agent against various tumors, it is currently approved in many countries for advanced soft-tissue sarcoma and renal cell carcinoma...

The anti-cancer drug pazopanib hydrochloride (PZH) has a very low aqueous solubility and a variable oral bioavailability. A new pharmaceutical formulation with an improved solubility may enhance the bioavailability and reduce the variability. A broad selection of polymer excipients was tested for their compatibility and solubilizing properties by conventional microscopic, thermal and spectrometric techniques. A wet milling and mixing technique was used to produce homogenous powder mixtures. The dissolution properties of the formulation were tested by a pH-switch dissolution model...

Secondary spontaneous pneumothorax almost always develops secondary to an underlying lung disease. A pneumothorax secondary to a malignancy is very rare, and is observed most frequently in soft tissue sarcomas. Pazopanib, a tyrosine kinase inhibitor, is used in metastatic soft tissue sarcomas treatment. The rate of pneumothorax that is caused by pazopanib is about 14% in the literature. The patient being presented in this article underwent surgery for soft tissue sarcoma, postoperatively received pazopanib (Votrient® 400 mg, oral, Glaxo Group Ltd, Brentford, UK) treatment due to widespread bilateral lung metastases, and developed synchronous spontaneous pneumothorax...

Pazopanib (Votrient®), an orally administered multi-targeted tyrosine kinase inhibitor that 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, is approved in the EU, the USA and other countries for the treatment of advanced renal cell carcinoma (RCC). In randomized controlled trials in patients with advanced, predominantly clear-cell RCC, pazopanib significantly improved progression-free survival (PFS) compared with placebo in both treatment-naïve and cytokine-pretreated patients and, as a first-line therapy, was noninferior to intermittent sunitinib with respect to PFS...

We analyzed the dynamics of the expression of transcription factors, VEGF and its receptor VEGFR2, serine-threonine protein kinase mTOR and activity of proteasome and calpain in patients with metastatic renal cancer during therapy with tyrosine kinase inhibitor Votrient and mTOR blocker Afinitor. The expression of hypoxic nuclear factor HIF-1α in the tumor tissue decreased during therapy with the target preparations. The decrease of VEGF and its receptor VEGFR2 was observed only in patients treated with mTOR inhibitor...

BACKGROUND: Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options...

Prior tumor cell studies have shown that the drugs sorafenib (Nexavar) and regorafenib (Stivarga) reduce expression of the chaperone GRP78. Sorafenib/regorafenib and the multi-kinase inhibitor pazopanib (Votrient) interacted with sildenafil (Viagra) to further rapidly reduce GRP78 levels in eukaryotes and as single agents to reduce Dna K levels in prokaryotes. Similar data were obtained in tumor cells in vitro and in drug-treated mice for: HSP70, mitochondrial HSP70, HSP60, HSP56, HSP40, HSP10, and cyclophilin A...

BACKGROUND: Recently, the phase III PALETTE study introduced pazopanib (Votrient®) as treatment for adult patients with locally advanced or metastatic non-liposarcoma soft tissue sarcoma after prior treatment with doxorubicin and/or ifosfamide. Pneumothorax was reported as adverse event in 8 of 246 treated patients (3.3%) in that study. This case series presents the incidence and clinic of this complication in the Leiden University Medical Centre. CASES: Forty-three patients were treated with pazopanib of which six patients (14...

Background: Pazopanib (PZP) may induce prolonged cardiac repolarization and proarrhythmic effects, similarly to other tyrosine kinase inhibitors. Objectives: To demonstrate PZP-induced prolonged cardiac repolarization and proarrhythmic electrophysiological effects and to investigate possible preventive effects of metoprolol and diltiazem on ECG changes (prolonged QT) in an experimental rat model. Methods: Twenty-four Sprague-Dawley adult male rats were randomly assigned to 4 groups (n = 6). The first group (normal group) received 4 mL of tap water and the other groups received 100 mg/kg of PZP (Votrient® tablet) perorally, via orogastric tubes...

Clear - cell renal cell carcinoma (ccRCC) is a histological subtype of renal cell carcinoma - the most prevalent adult kidney cancer. Causes of ccRCC are not completely understood and therefore number of available therapies is limited. As a consequence of tumor chemo- and radioresistance as well as restrictions in offered targeted therapies, overall response rate is still unsatisfactory. Moreover, a significant group of patients (circa 1/4) does not respond to the targeted first-line treatment, while in other cases, after an initial period of stable improvement, disease progression occurs...

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)...

Renal cell carcinoma is the most common type of kidney cancer in adults. It accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. At the moment several biological agents are used for the treatment of metastatic renal cell carcinoma. We describe the case of a man who has been treated with pazopanib (Votrient) for metastatic renal cell carcinoma since July 2011. At the time of writing, the patient is still receiving treatment (29 months) and is showing a long-lasting response with a favorable safety profile...

Metastatic melanoma has a median length of survival after diagnosis of 6-9 months. Unfortunately, the National Comprehensive Cancer Network clinical practice guidelines for treating stage IV, unresectable, metastatic melanoma are limited with regard to treatment options. Pazopanib (Votrient™) is FDA-approved for advanced soft tissue sarcoma and advanced renal cell carcinoma. Limited research exists for using pazopanib in the treatment of metastatic melanoma. We present five cases in which pazopanib was used in combination with paclitaxel ± carboplatin for treatment of unresectable, metastatic melanoma...

Pazopanib (Votrient™, GlaxoSmithKline), a multi-kinase inhibitor with activity against VEGFR and other receptors, was recently approved by the FDA for the treatment of advanced renal cell carcinoma (RCC). Here, we review the history of its development, together with an overview of VEGF and its receptors and co-receptors. Results from selected clinical trial data in RCC and other malignant diseases are presented. Based on available evidence, pazopanib is an effective VEGFR inhibitor with demonstrable clinical activity in metastatic RCC and promising activity in other diseases...