Pazopanib hydrochloride has been approved by the US FDA for the treatment of kidney cancer. The drug is marketed in the US under the trade name Votrient®.

Pazopanib hydrochloride was developed by GlaxoSmithKline. The drug, which is administered orally in tablet form, received formal approval from the Food and Drug Administration (FDA) for treating advanced kidney cancer (renal cell carcinoma) in October 2009.

Each year more than 58,000 adults in the United States are diagnosed with renal cell carcinoma (RCC), the most common form of kidney cancer. It is also called conventional or clear cell renal cell carcinoma. This condition is responsible for 85% of all kidney cancers and kills more than 13,000 Americans annually. Slightly more blacks and those of northern European ancestry are susceptible, but no race is immune. About twice as many men as women will contract the disease and the median age is 64. In this country, renal cell cancer is the 10th leading cause of death by cancer in adult males.

While the specific cause of renal cell carcinoma is unknown, its method of operation is understood as are the risk factors that seem to contribute to its development. Cancerous cells take up residence in the lining of the tinier tubules in the kidney. From there, abnormal cells rapidly multiply, eventually forming a mass or tumor that robs surrounding organs and tissues of O2 and vital nutrients. Cells may also break off and float through the bloodstream or lymphatic system. The most common destinations are the lungs, liver, bones and brain, but the colon and pancreas can also be invaded. Survival depends to a great extent on how early the cancerous condition is detected and the amount of metastasis.

FDA approval of pazopanib followed an international, multi-center trial against a placebo (an inactive drug). This was the type of drug trial in which neither the patient nor the treating physician knows if they are being given the test compound or the placebo. A randomized trial ascribes patients from the eligible pool (for each stage of a study) to the placebo or treatment group on a random basis – it is intended to reduce the chances of subjective bias being introduced to the trial.

The study involved two groups of patients with renal cell carcinoma: those who were previously treated with cytokine therapy and a second group which had not. 435 patients were enrolled in the study; of these, 290 received the drug and 190 were given a placebo. The study measured the whether the cancer patients got worse (specificaly the length of time during or after treatment that a patient’s disease does not worsen). Patients receiving pazopanib had a median PFS of 9.2 months compared to 4.2 months for those in the placebo group (irrespective of prior cytokine therapy). At the end of the study period, 40% of the patients that had participated in the trial had died. However, the response rate (the percentage that showed a partial or a total remission of their cancer) for patients treated with pazopanib was 30%. This figure was 3% for those patients who had received a placebo. In this study, scientists measured how long the tumor shrank before it began to grow again – the so-called “duration of response”. The median duration in this study was 13.5 months.

According to the FDA report, the two groups had statistically different rates of adverse reactions. The adverse reactions included abnormal liver function, high blood pressure, diarrhea, and too much protein in the urine. Cardiac issues – as measured by altered EEG readings – have been reported with pazopanib. This type of reaction happens with some other drugs, too.

The report notes that two deaths in the study were associated with liver failure. As a consequence of this, Pazopanib’s official product label warns about possible hepatic dysfunction. For this reason FDA advises that liver function tests be conducted every month at the start of treatment and periodically thereafter. In patients with a history of liver problems, or abnormal results, the manufacturer provides recommendations for dose modification. The FDA also recommends that doctors monitor heart function and electrolytes during treatment.

Mode of Action

For a hard tumour to grow, it needs to have an adequate blood supply. Vascular endothelial growth factor (VEGF) is a cytokine (a cellular messenger) which stimulates the growth of new blood vessels. Its role in healthy individuals is to help to restore the oxygen supply to tissues when the blood supply is inadequate. If cancer cells can express vascular endothelieal growth factor, they are able to get the blood supply that they need to grow and metastasise to other parts of the body

Pazopanib works by inhibiting tyrosine kinase. It is considered to be a second-generation tyrosine kinase inhibitor and is active against on vascular endothelial growth factor receptor-1,-2, and-3, platelet-derived growth factor receptor-a, platelet-derived growth factor receptor-ß, and c-kit. In pre-clinical studies, it was shown to have excellent antiangiogenic (inhibiting the growth of new blood vessels) and antitumor activity. At a biochemical level, the drug seems to work by binding to the adenosine triphosphate enzymatic pocket.

Pazopanib has been specifically approved by the government for the treatment of patients with renal cell cancer (advanced stage). Kidney cancer patients who have already been given some other treatment are also approved for Pazopanib.

Kidney Cancer

According to the National Cancer Institute, approximately 58000 Americans were diagnosed with kidney cancer in 2010 and some 13000 deaths were attributed to the illness.

In adults, there are two main types of cancer affecting the kidneys: renal pelvis carcinoma and renal cell carcinoma. In renal pelvis carcinoma, the cancer forms in the centre of the kidney where a patients’ urine collects.

Renal cell carcinoma forms in the lining of the nephrons (the small tubes within the kidneys which are responsible for filtering the blood and removing waste products from it). Renal cell carcinoma is the most common for of kidney cancer seen in adults, accounting for more than 90% of cases. There are six agentsavailable for treatment of metastatic RCC.

Common risk factors include:

• Von Hippel-Lindeau disease results in renal cell cancer 40% of the time.
• Smoking doubles the chance of developing this condition.
• Obesity in women seems to be an indicator.
• Tuberous sclerosis
• Renal transplant patients are at higher risk as are those who have experienced long term kidney dialysis.
• Occupational exposure to chemicals, asbestos and other toxic products
• Hypertension
• Horseshoe kidney
• Family history and genetics is also an important key factor.

Unfortunately, it is possible to have renal cell carcinoma and exhibit no obvious symptoms, a fact that greatly frustrates early detection and successful treatment. Only 10% of those patients who are diagnosed with this condition present classic symptoms. The most serious warnings, for which medical attention should be obtained include a pain in the side that does not disappear, blood in the urine, a lump or swelling in the abdomen or side, unrelenting fever, night sweats and/or unexplained weight loss. Other possible symptoms are back pain, enlargement of veins around the testicles, excessive hair growth on women, fatigue, loss of appetite and general malaise.

The first step to treatment of this condition is identification through a medical interview followed by a physical exam. X-rays, CT scans, blood work and other lab tests will be conducted. If a mass is present, a biopsy will be conducted to further verify the condition. Staging that includes more lab tests and imaging studies will determine the extent of the cancer and the course of treatment.

Chemical Composition

The scientificl name of Pazopanib is:
5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzene-sulfonamide mono-hydrochloride (as the hydrochloride salt).

The molecular formula of the drug is C21H23N7O2S•HCl and it has a molecular weight of 473.99.  Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 1 (meaning that it will dissolve in the stomach) and it is practically insoluble above pH 4 in aqueous media.

Alternative Uses for Pazopanib

Currently, Pazopanib is only approved for the treatment of renal cell carcinoma. However, its mode of action, inhibition of VEGF means that it could be expected to have a role in combating other types of cancer.

The manufacturer (GlaxoSmithKline) has sponsored a phase 1 clinical study in which Pazopanib was combined with chemotherapy agents (a) TAXOL; (b) TAXOL and PARAPLATIN; and (c) TAXOL and lapatinib, in patients suffering from solid tumour cancers. The study has been completed, but the data has yet to be released.

The efficacy of the drug, on its own or in combination with other compounds, is being studied (or is planned) in the treatment of a wide range of diseases and conditions including: breast cancer; advanced solid tumours; certain types of lung cancer; liver cancer; ovarian cancer; multiple myeloma; prostate cancer; neuroendocrine cancer; unresectable melanoma; thyroid cancer and as a treatment for macular degeneration (an eye condition). A clinical trial of pazopanib eye drops for macular degeneration found it had some efficacy but only for patients with a certain genotype.

Pazopanib also seems to have inhibitory activity in xenografts and could prove useful for treatments of conditions other than cancer, although much research needs to be done in this field before the drug sees use.

Therapeutic Dosage

Pazopanib hydrochloride is a drug used for chemotherapy of cancer and must be administered by a suitably qualified medical practitioner or oncologist. Unlike old-style chemotherapy drugs, Pazopanib is given orally. The drug is supplied as either 200 or 400 mg film-coated tablets which should be swallowed whole. The normal dosage is 800 mg, administered orally once per day. The medicine should be taken without food; either at least an hour before or two hours after eating.

Be sure to talk with your healthcare provider about taking this medication. Many treatment centers have oncology nurses that are well trained and experienced working with cancer patients. Make sure to ask about storing the Pazopanib at home, maintaining a regular schedule, and what to do if you miss a dose.

If the drug is not well-tolerated by an individual, it can be modified (decreased) in 200 mg increments as a means of managing adverse reactions. The maximum dose of Pazopanib should not exceed 800 mg per day.

In clinical studies, one in five patients noted mild adverse reactions during treatment: diarrhoea, hypertension, hair colour changes, nausea, anorexia, and vomiting.

Be sure to tell your doctors about all the drugs you take regularly, including over-the-counter drugs. This advice applies to all drugs all the time, not just to Pazopanib. Also, be sure to tell your healthcare providers about any allergy you have. Further, if you have surgery after you start taking Pazopanib, for any reason (not just cancer), tell your doctor you take this medication. That goes for dental surgery, too.

Currently, Pazopanib is not approved for use in paediatric medicine since adequate data on its safety and efficacy in treating children has yet to be established.

Although oral chemotherapy agents like Pazopanib tend to have fewer side effects than old-style intravenous drugs, there are potential side effects. Medline Plus has a good list of potential side effects.

In clinical trials abnormalities people who took pazopanib tended to have: increased liver enzymes, leukopenia, too much blood sugar, deficiency in white blood cells, hypophosphatemia, thrombocytopenia, lymphocytopenia, low levels of sodium, phosphate, and magnesium in the blood.

Possible fatalities (worst case) on pazopanib could be due to strokes, gastric cancer, gastrointestinal hemorrhage, bowel perforation, cardiac failure, heart attack, liver failure and pneumonia.

Other treatment of RCC

Renal cell carcinoma is usually not effectively cured by either chemotherapy or radiation episodes. The surgical removal of part or all of the diseased kidney may also include the bladder, surrounding tissues and lymph nodes, depending upon the amount of metastasis. Either a simple, partial or radical nephrectomy will be done through a large abdominal incision or a smaller, laparoscopic procedure. Hormone treatments have been shown to reduce tumor growth. Newer drug therapies include sorafenib, sunitinib, temsirolimus and bevacizumab.

Unless all cancer is removed, a patient is not considered cured. Relapse is possible. The survival rate for early detection of non-spreading Stage I renal cell cancer is 64%–66%. By Stage IV cancer level, the survival rate has dropped to 11%. Patients tend not to live long once the cancer starts spreading outside the kidney. New research continues to look for more effective treatments for this condition.