Anticancer agent - pazopanib
For a tumour to grow and thrive, it has to develop a network of blood vessels that meshes into the body's vessels.
For a tumour to grow and thrive, it has to develop a network of blood vessels that meshes into the body's vessels.
This angiogenesis process has provided a whole host of anticancer drug targets, including cytokines such as vascular endothelial growth factor (VEGF). Roche's Avastin is a monoclonal antibody drug that targets VEGF, and more than 30 small molecule drugs acting on VEGF are also in development. One of these is GlaxoSmithKline's pazopanib.
A dose escalating Phase I study was carried out in 28 patients with solid tumours.1 Subjects were given daily oral doses of 50, 100, 200 and 400 mg, and plasma concentrations reached the levels shown to have antitumour and antiangiogenic effects in preclinical studies. It was well tolerated.
In a second Phase I trial, 43 patients with solid tumours were given escalating doses of pazopanib, from 50mg three times a week to 2,000mg once a day, to investigate its safety, tolerability and pharmacokinetics.2 It had a mean half-life of 35h, and doses of at least 800mg once a day gave maximum exposure to the drug. The maximum tolerated dose was not reached. Six patients achieved stable disease for at least six months, and four had a minimal response of tumour shrinkage.
A further study in 33 patients with solid tumours looked at its safety and pharmacokinetics in once daily doses in combination with lapatinib at various levels.3 The regime was generally well tolerated, with the most common side effects being nausea, vomiting, fatigue and diarrhoea. Ten of the patients experienced prolonged disease stabilisation for more than 16 weeks and three - one with giant cell tumour of the bone and two with renal cell cancer - had stable disease. Development continues, and numerous trials are ongoing in various forms of cancer.