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.

Pharmacokinetics

Absorption/Distribution

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%.

Biotransformation/Metabolism

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

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

External links

For extended ADME data see the following: Electronic Medicines Compendium (eMC) Drugs.com European Medicines Agency (EMA)