- Guide to PHARMACOLOGY
Synonyms: GW 786034 | indazolylpyrimidine 13  | Votrient®
pazopanib is an approved drug (FDA (2009), EMA (2010))
Compound class: Synthetic organic
Comment: Pazopanib is a Type-1 kinase inhibitor. Its discovery is reported in . It targets multiple receptor tyrosine kinases (VEGFR1, VEGFR2, VEGFR3, PDGFRβ, FGFR1, Kit and CSF1R).
Ligand Activity Visualisation Charts
These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.✖
View more information in the IUPHAR Pharmacology Education Project: pazopanib
|No information available.
|Summary of Clinical Use
|Used in the treatment of advanced renal cell cancer and advanced soft tissue sarcoma.
Marketed formulations contain pazopanib hydrochloride (PubChem CID 11525740).
|Mechanism Of Action and Pharmacodynamic Effects
|Pazopanib (a synthetic indazolylpyrimidine) is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α and PDGFR-β, fibroblast growth factor receptor (FGFR)-1 and FGFR-3, cytokine receptor, interleukin-2 receptor inducible T-cell kinase, leukocyte-specific protein tyrosine kinase, and transmembrane glycoprotein receptor tyrosine kinase. Many of these receptor targets are part of the pathway involved in neoangiogenesis in tumours and are essential for tumour survival and growth. Pazozanib can reach circulating concentrations of >15µg/ml which is sufficient to elicit significant alterations in indicators of tumour regression (reduction in tumour blood flow, increased tumour apoptosis, inhibition of tumour growth, reduction in tumour interstitial fluid pressure, and hypoxia in cancer cells) in patients undergoing treatment.
|Maximum plasma concentration is reached in 2-4h following oral administration. The major circulating component of the drug is pazopanib, and not its metabolites. Bioavailability may be low due to incomplete absorption from the gastrointestinal tract. Bioavailability can be increased by administering as a crushed tablet and if taken before or after eating. Protein binding is greater than 99%.
|Metabolized in the liver mainly by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C8. Only one of its metabolites can inhibit the proliferation of VEGF-stimulated HUVEC cells with a similar potency to that of the parent compound, but as this constitutes a very small proportion of the administered dose in the system, it is assumed that the activity of pazopanib is mainly dependent on parent pazopanib exposure.
|Elimination is primarily via feces (82.2%) with <4% in the urine.
|Organ function impairment
|Renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib as less than 4% is eliminated via the kidneys although due to a lack of experience in this group, caution is advised in patients with creatinine clearance below 30 ml/min. Based on safety and tolerability data, the dosage of pazopanib should be reduced to 200 mg once daily in subjects with moderate hepatic impairment. As a result of diminished exposure and limited hepatic reserve pazopanib is not recommended in patients with severe hepatic impairment
For extended ADME data see the following:
Electronic Medicines Compendium (eMC)
European Medicines Agency (EMA)