Pazopanib

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Pazopanib
Pazopanib.svg
Clinical data
Pronunciation /pæˈzpənɪb/ paz-OH-pə-nib
Trade names Votrient
AHFS/Drugs.com Monograph
MedlinePlus a610013
License data
Pregnancy
category
  • AU:D
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 21% (14–39%) [1]
Protein binding >99.5% [1] [2]
Metabolism Liver: CYP3A4 (major), 1A2 and 2C8 (minor) [2]
Elimination half-life 30.9±4 hours [1]
Excretion Faeces (primary), urine (<4%) [2]
Identifiers
  • 5-({4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H23N7O2S
Molar mass 437.52 g·mol−1
3D model (JSmol)
  • O=S(=O)(N)c1c(ccc(c1)Nc2nccc(n2)N(c4ccc3c(nn(c3C)C)c4)C)C
  • InChI=1S/C21H23N7O2S.ClH/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16;/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25);1H Yes check.svgY
  • Key:MQHIQUBXFFAOMK-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Pazopanib, sold under the brand name Votrient, is an anti-cancer medication marketed worldwide by Novartis. It is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide. [3] [4] [5] [6]

Contents

Medical uses

It is approved by numerous regulatory administrations worldwide, including the US Food and Drug Administration (FDA) (19 October 2009), the European Union's European Medicines Agency (EMA) (14 June 2010), the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) (14 June 2010) and Australia's Therapeutic Goods Administration (TGA) (30 June 2010), for use as a treatment for advanced/metastatic renal cell carcinoma and advanced soft tissue sarcomas. [2] [3] [4] [5] [6] In Australia and New Zealand, it is subsidised under the Pharmaceutical Benefits Scheme (PBS) and by Pharmac respectively, under a number of conditions, including: [7] [8]

Pazopanib has also demonstrated initial therapeutic properties in patients with aggressive fibromatosis (desmoid tumor), [9] ovarian and non-small cell lung cancer. [10] [ unreliable medical source? ] However, plans to apply to the EMA for a variation to include advanced ovarian cancer have been withdrawn and a license will not be sought in any country. [11] [12]

Contraindications

The only contraindication is hypersensitivity to pazopanib or any of its excipients. [5] Cautions include: [2]

It has one black box warning by the US FDA, namely severe hepatotoxicity including fatalities. [2] [3]

Adverse effects

The most common side effects of pazopanib are nausea, vomiting, diarrhoea (occurs in about half of patients), changes in hair colour, hypertension (which usually occurs during the first few weeks of treatment), appetite loss, hyperglycaemia, hypoglycaemia, electrolyte abnormalities (including hypocalcaemia, hypomagnesemia, hypophosphatemia), laboratory anomalies (including increased AST, ALT and protein in the urine), oedema, hair loss or discolouration, taste changes, abdominal pain, rash, fatigue and bone marrow suppression (including leucopenia, neutropenia, thrombocytopenia and lymphopenia). [13] It has been associated with a low, but real risk of potentially fatal liver damage. [13]

Overdose

The treatment for overdose is purely supportive and the symptoms include grade 3 hypertension and fatigue. [5]

Interactions

Drug interactions include: [2]

Pharmacology

Mechanism of action

Pazopanib is a multiple kinase inhibitor that limits tumor growth by targeting angiogenesis via inhibition of enzymes including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-KIT and FGFR. [2] [13] [16] [17] [18] [19]

Pharmacokinetics

After oral intake of a single tablet, pazopanib has a bioavailability of 21% with a range of 14–39% between people. It reaches highest concentrations in the blood plasma after median 3.5 hours; the range in studies was 1.0 to 11.9 hours. When taken regularly, the area under the curve (AUC) increases 1.23- to 4-fold as compared to a single dose. Taking the drug together with food approximately doubles the AUC as well as the highest plasma concentrations (Cmax); and crushing the tablet increases the AUC 1.46-fold, as well doubling the Cmax. [1] [4]

When in the bloodstream, more than 99.5% of the substance are bound to plasma proteins. The liver enzyme mainly responsible for metabolizing the drug is CYP3A4; and there are minor contributions from CYP1A2 and CYP2C8. Metabolites identified in tests with human liver cells and microsomes include various hydroxyl derivatives and possibly a carboxylic acid. Only 6% of the circulating substance is in the form of metabolites, and all but one of them are 10- to 20-fold less active than pazopanib itself. Consequently, the metabolites are not considered important for the drug's therapeutic effect. [1] [4]

Pazopanib is eliminated with a biological half-life of 30.9±4 hours on average (range 21–51 hours) mainly via the faeces. Less than 4% are eliminated via the urine. [1] [4]

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References

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  2. 1 2 3 4 5 6 7 8 "Votrient (pazopanib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 27 January 2014.
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