Pazopanib

Last updated

Pazopanib
Pazopanib.svg
Clinical data
Pronunciation /pæˈzoʊpənɪb/ 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]

Related Research Articles

<span class="mw-page-title-main">Imatinib</span> Chemical compound

Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome–positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.

<span class="mw-page-title-main">Gemcitabine</span> Chemical compound

Gemcitabine, sold under the brand name Gemzar, among others, is a chemotherapy medication used to treat cancers. It is used to treat testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by intravenous infusion. It acts against neoplastic growth, and it inhibits the replication of Orthohepevirus A, the causative agent of Hepatitis E, through upregulation of interferon signaling.

<span class="mw-page-title-main">Erlotinib</span> Medication for treatment of non-small-cell lung cancer

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

<span class="mw-page-title-main">Sorafenib</span> Chemical compound

Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer, advanced primary liver cancer, FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

<span class="mw-page-title-main">Nilotinib</span> Chemical compound

Nilotinib, sold under the brand name Tasigna marketed worldwide by Novartis, is a medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome. It may be used both in initial cases of chronic phase CML as well as in accelerated and chronic phase CML that has not responded to imatinib. It is taken by mouth.

<span class="mw-page-title-main">Vandetanib</span> Chemical compound

Vandetanib, sold under the brand name Caprelsa, is an anti-cancer medication that is used for the treatment of certain tumours of the thyroid gland. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor, the epidermal growth factor receptor, and the RET-tyrosine kinase. The drug was developed by AstraZeneca who later sold the rights to Sanofi in 2015.

<span class="mw-page-title-main">Mesoblastic nephroma</span> Medical condition

Congenital mesoblastic nephroma, while rare, is the most common kidney neoplasm diagnosed in the first three months of life and accounts for 3-5% of all childhood renal neoplasms. This neoplasm is generally non-aggressive and amenable to surgical removal. However, a readily identifiable subset of these kidney tumors has a more malignant potential and is capable of causing life-threatening metastases. Congenital mesoblastic nephroma was first named as such in 1967 but was recognized decades before this as fetal renal hamartoma or leiomyomatous renal hamartoma.

<span class="mw-page-title-main">Axitinib</span> Chemical compound

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

<span class="mw-page-title-main">ROS1</span> Protein-coding gene in the species Homo sapiens

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.

<span class="mw-page-title-main">Epithelioid sarcoma</span> Medical condition

Epithelioid sarcoma is a rare soft tissue sarcoma arising from mesenchymal tissue and characterized by epithelioid-like features. It accounts for less than 1% of all soft tissue sarcomas. It was first definitively characterized by F.M. Enzinger in 1970. It commonly presents itself in the distal limbs of young adults as a small, soft mass or a cluster of bumps. A proximal version has also been described, frequently occurring in the upper extremities. Less commonly, cases are reported in the pelvis, vulva, penis, and spine.

<span class="mw-page-title-main">Bosutinib</span> Chemical compound

Bosutinib, sold under the brand name Bosulif, is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.

<span class="mw-page-title-main">Afatinib</span> Chemical compound

Afatinib, sold under the brand name Gilotrif among others, is a medication which is used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.

<span class="mw-page-title-main">Apatinib</span> Chemical compound

Apatinib, also known as rivoceranib, is a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2. It is an orally bioavailable, small molecule agent which is thought to inhibit angiogenesis in cancer cells; specifically, apatinib inhibits VEGF-mediated endothelial cell migration and proliferation thus blocking new blood vessel formation in tumor tissue. This agent also mildly inhibits c-Kit and c-SRC tyrosine kinases.

<span class="mw-page-title-main">Tivozanib</span> Medication

Tivozanib, sold under the brand name Fotivda, is a medication used for the treatment of advanced renal cell carcinoma. It is an oral VEGF receptor tyrosine kinase inhibitor.

<span class="mw-page-title-main">Cabozantinib</span> Chemical compound

Cabozantinib, sold under the brand names Cometriq and Cabometyx among others, is an anti-cancer medication used to treat medullary thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. It is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and also inhibits AXL and RET. It was discovered and developed by Exelixis Inc.

<span class="mw-page-title-main">Abemaciclib</span> Anti-breast cancer medication

Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.

Members of the Organo Anion Transporter (OAT) Family are membrane transport proteins or 'transporters' that mediate the transport of mainly organic anions across the cell membrane. Therefore, OATPs are present in the lipid bilayer of the cell membrane, acting as the cell's gatekeepers. OATPs belong to the Solute Carrier Family (SLC) and the major facilitator superfamily.

VEGFR-2 inhibitor, also known as kinase insert domain receptor(KDR) inhibitor, are tyrosine kinase receptor inhibitors that reduce angiogenesis or lymphangiogenesis, leading to anticancer activity. Generally they are small, synthesised molecules that bind competitively to the ATP-site of the tyrosine kinase domain. VEGFR-2 selective inhibitor can interrupt multiple signaling pathways involved in tumor, including proliferation, metastasis and angiogenesis.

References

  1. 1 2 3 4 5 6 "CHMP Assessment Report: Votrient (pazopanib)" (PDF). European Medicines Agency. Retrieved 8 October 2016.
  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.
  3. 1 2 3 "Votrient- pazopanib hydrochloride tablet, film coated". DailyMed. 17 August 2020. Retrieved 9 November 2020.
  4. 1 2 3 4 5 "Votrient : EPAR - Product Information" (PDF). European Medicines Agency. Glaxo Group Ltd. 23 January 2014. Retrieved 27 January 2014.
  5. 1 2 3 4 "Votrient 200 mg and 400 mg film coated tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. GlaxoSmithKline UK. 20 December 2013. Retrieved 27 January 2014.
  6. 1 2 "Product Information Votrient Tablets" (PDF). TGA eBusiness Services. GlaxoSmithKline Australia Pty Ltd. 25 March 2013. Retrieved 27 January 2014.
  7. ↑ "Pharmaceutical Benefits Scheme (PBS) - Pazopanib". Pharmaceutical Benefits Scheme. Australian Government. Retrieved 27 January 2014.
  8. ↑ "Pazopanib - Online Pharmaceutical Schedule". Pharmaceutical Management Agency. Retrieved 9 June 2015.
  9. ↑ Mangla A, Agarwal N, Schwartz G (February 2024). "Desmoid Tumors: Current Perspective and Treatment". Current Treatment Options in Oncology. 25 (2): 161–175. doi: 10.1007/s11864-024-01177-5 . PMC   10873447 . PMID   38270798.
  10. ↑ "Pazopanib shows encouraging activity in several tumour types, including soft tissue sarcoma and ovarian cancer". FierceBiotech. 2008-09-15. Retrieved 2010-08-10.
  11. ↑ "GSK pulls bid to extend use of kidney drug to ovarian cancer". Reuters. 31 March 2014. Archived from the original on March 7, 2016. Retrieved 7 April 2014.
  12. ↑ "Regulatory update: Votrient (pazopanib) as maintenance therapy for advanced ovarian cancer in the EU". GlaxoSmithKline. 31 March 2014. Archived from the original on 8 April 2014. Retrieved 7 April 2014.
  13. 1 2 3 Zivi A, Cerbone L, Recine F, Sternberg CN (September 2012). "Safety and tolerability of pazopanib in the treatment of renal cell carcinoma". Expert Opinion on Drug Safety. 11 (5): 851–859. doi:10.1517/14740338.2012.712108. PMID   22861374. S2CID   2178331.
  14. ↑ Khurana V, Minocha M, Pal D, Mitra AK (March 2014). "Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions. 29 (3): 179–190. doi:10.1515/dmdi-2013-0062. PMC   4407685 . PMID   24643910.
  15. ↑ Khurana V, Minocha M, Pal D, Mitra AK (May 2014). "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions. 29 (4): 249–259. doi:10.1515/dmdi-2014-0014. PMC   4407688 . PMID   24807167.
  16. ↑ Verweij J, Sleijfer S (May 2013). "Pazopanib, a new therapy for metastatic soft tissue sarcoma". Expert Opinion on Pharmacotherapy. 14 (7): 929–935. doi:10.1517/14656566.2013.780030. PMID   23488774. S2CID   5063031.
  17. ↑ Schöffski P (June 2012). "Pazopanib in the treatment of soft tissue sarcoma". Expert Review of Anticancer Therapy. 12 (6): 711–723. doi:10.1586/era.12.41. PMID   22716487. S2CID   1738165.
  18. ↑ Pick AM, Nystrom KK (March 2012). "Pazopanib for the treatment of metastatic renal cell carcinoma". Clinical Therapeutics. 34 (3): 511–520. doi:10.1016/j.clinthera.2012.01.014. PMID   22341567.
  19. ↑ Rimel BJ (April 2015). "Antiangiogenesis agents in ovarian cancer". Contemporary Oncology. 7 (2): 16–19.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.