Pazopanib

Key takeaways

Pazopanib belongs to science; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Pazopanib to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Pazopanib from memory before moving on to harder problems.

Reference excerpt

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.

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:

The medication is used to treat clear cell renal cell carcinoma, the most common histological subtype. The treatment phase is continuing treatment beyond three months. The patient has been issued an authority prescription for pazopanib. The patient must have stable or responding disease according to the Response Evaluation Criteria In Solid Tumours (RECIST). This treatment must be the sole tyrosine kinase inhibitor subsidised for this condition. 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 However, plans to apply to the EMA for a variation to include advanced ovarian cancer have been withdrawn and a license will not be sought in any country.

Contraindications The only contraindication is hypersensitivity to pazopanib or any of its excipients. Cautions include:

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

Adverse effects

It has one boxed warning by the US FDA, namely severe hepatotoxicity including fatalities. 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.

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

Interactions Drug interactions include:

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. CYP3A4 inducers (e.g. rifampin, carbamazepine) decrease pazopanib serum levels. It is a p-glycoprotein (PGP) substrate and hence PGP inhibitors such as quinidine may interact with pazopanib. Pazopanib is not a substrate for either of the liver enzymes OATP1B1 and OATP1B3. Pazopanib has inhibitory potency towards OATP1B1 but not for OATP1B3.

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.

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. 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. 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.

References

Worked examples

Example 1 — a first encounter with Pazopanib

Start with the simplest possible case. Write down what Pazopanib claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In science, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Pazopanib before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Pazopanib ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Pazopanib

In research: Pazopanib appears in science research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Pazopanib in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Pazopanib is common in secondary-school and first-year university syllabi. It links to neighbouring topics Aminopyrimidines, Anilines, Drugs developed by GSK plc, so understanding it makes those chapters shorter.
In everyday life: Look for Pazopanib outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study Pazopanib in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Pazopanib means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Pazopanib out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Pazopanib in simple terms?

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.

Why does Pazopanib matter?

Because it connects several science ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Pazopanib?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Pazopanib.