Pazopanib

Overview

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.[1–4] WP

Uses, dosage and effects

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. In Australia and New Zealand, it is subsidised under the Pharmaceutical Benefits Scheme (PBS) and by Pharmac respectively, under a number of conditions, including:[1–7] WP

• The medication is used to treat clear cell renal cell carcinoma, the most common histological subtype.[1–7] WP
• The treatment phase is continuing treatment beyond three months.[1–7] WP
• The patient has been issued an authority prescription for pazopanib.[1–7] WP
• The patient must have stable or responding disease according to the Response Evaluation Criteria In Solid Tumours (RECIST).[1–7] WP
• This treatment must be the sole tyrosine kinase inhibitor subsidised for this condition.[1–7] WP

Pazopanib has also demonstrated initial therapeutic properties in patients with aggressive fibromatosis (desmoid tumor), ovarian and non-small cell lung cancer. However, plans to apply to the EMA for a variation to include advanced ovarian cancer have been withdrawn and a license will not be sought in any country.[8–11] WP⚠ Wikipedia itself has flagged this text: unreliable medical source?.

Risks and side effects

Contraindications

The only contraindication is hypersensitivity to pazopanib or any of its excipients. Cautions include:[3][5] WP

• Hypertension, including hypertensive crises have been reported.[3][5] WP
• QT interval prolongation and torsades de pointes have been reported.[3][5] WP
• Thrombotic microangiopathy has been reported.[3][5] WP
• Thrombotic thrombocytopenic purpura has been reported.[3][5] WP
• Haemolytic uremic syndrome has been reported.[3][5] WP
• Haematologic parameter alterations have been reported in 31–37% of patients.[3][5] WP
• Events of cardiac dysfunction (decreased left ventricular ejection fraction and congestive heart failure) have been observed.[3][5] WP
• Fatal haemorrhage, arterial and venous thrombotic events and perforations in the gastrointestinal tract have been observed in randomized clinical trials.[3][5] WP

Adverse effects

It has one boxed warning by the US FDA, namely severe hepatotoxicity including fatalities.[1][5] WP

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). It has been associated with a low, but real risk of potentially fatal liver damage.[12] WP

Overdose

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

Interactions

Interactions

Drug interactions include:[5] WP

• Co-administration with strong inhibitors of the liver enzyme CYP3A4 (e.g. ketoconazole, ritonavir, clarithromycin, grapefruit juice) may increase pazopanib serum levels as it is a CYP3A4 substrate.[5] WP
• CYP3A4 inducers (e.g. rifampin, carbamazepine) decrease pazopanib serum levels.[5] WP
• It is a p-glycoprotein (PGP) substrate and hence PGP inhibitors such as quinidine may interact with pazopanib.[5] WP
• Pazopanib is not a substrate for either of the liver enzymes OATP1B1 and OATP1B3.[13] WP
• Pazopanib has inhibitory potency towards OATP1B1 but not for OATP1B3.[14] WP

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.[5][12][15–18] WP

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.[2][19] WP

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.[2][19] WP

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.[2][19] WP

Chemistry

Formula

C21H24ClN7O2S PC

Formula (Wikipedia infobox)

C21H23N7O2S WP⚠ Wikipedia and PubChem give different formulas. Both are shown as each source has it.

CAS number

635702-64-6 PC

Molar mass (g/mol)

474.0 PC

IUPAC name (computed by PubChem)

5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide;hydrochloride PC

SMILES

CC1=C(C=C(C=C1)NC2=NC=CC(=N2)N(C)C3=CC4=NN(C(=C4C=C3)C)C)S(=O)(=O)N.Cl PC

InChIKey

MQHIQUBXFFAOMK-UHFFFAOYSA-N PC

PubChem CID

11525740

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Votrient- pazopanib hydrochloride tablet, film coated. 17 August 2020
2. Journal / agency Votrient: EPAR - Product Information. 23 January 2014
3. Other Votrient 200 mg and 400 mg film coated tablets - Summary of Product Characteristics (SPC). 20 December 2013
4. Other Product Information Votrient Tablets. 25 March 2013
5. Other Votrient (pazopanib) dosing, indications, interactions, adverse effects, and more
6. Other Pharmaceutical Benefits Scheme (PBS) - Pazopanib
7. Other Pazopanib - Online Pharmaceutical Schedule
8. Journal / agency Mangla A, Agarwal N, Schwartz G. Desmoid Tumors: Current Perspective and Treatment. Current Treatment Options in Oncology. February 2024. doi:10.1007/s11864-024-01177-5 · PMID 38270798 · PMC10873447
9. Other Pazopanib shows encouraging activity in several tumour types, including soft tissue sarcoma and ovarian cancer. 15 September 2008
10. Other GSK pulls bid to extend use of kidney drug to ovarian cancer. 31 March 2014
11. Other Regulatory update: Votrient (pazopanib) as maintenance therapy for advanced ovarian cancer in the EU. 31 March 2014
12. Journal / agency Zivi A, Cerbone L, Recine F, Sternberg CN. Safety and tolerability of pazopanib in the treatment of renal cell carcinoma. Expert Opinion on Drug Safety. September 2012. doi:10.1517/14740338.2012.712108 · PMID 22861374
13. Journal / agency Khurana V, Minocha M, Pal D, Mitra AK. Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors. Drug Metabolism and Drug Interactions. March 2014. doi:10.1515/dmdi-2013-0062 · PMID 24643910 · PMC4407685
14. Journal / agency Khurana V, Minocha M, Pal D, Mitra AK. Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors. Drug Metabolism and Drug Interactions. May 2014. doi:10.1515/dmdi-2014-0014 · PMID 24807167 · PMC4407688
15. Journal / agency Verweij J, Sleijfer S. Pazopanib, a new therapy for metastatic soft tissue sarcoma. Expert Opinion on Pharmacotherapy. May 2013. doi:10.1517/14656566.2013.780030 · PMID 23488774
16. Journal / agency Schöffski P. Pazopanib in the treatment of soft tissue sarcoma. Expert Review of Anticancer Therapy. June 2012. doi:10.1586/era.12.41 · PMID 22716487
17. Journal / agency Pick AM, Nystrom KK. Pazopanib for the treatment of metastatic renal cell carcinoma. Clinical Therapeutics. March 2012. doi:10.1016/j.clinthera.2012.01.014 · PMID 22341567
18. Journal / agency Rimel BJ. Antiangiogenesis agents in ovarian cancer. Contemporary Oncology. April 2015
19. Journal / agency CHMP Assessment Report: Votrient (pazopanib)

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.