Vorinostat

Vorinostat is a prescription drug used to treat cutaneous T cell lymphoma (CTCL). CTCL is a cancer that affects the skin. It is a rare disease; approximately four new cases are diagnosed for every one million people. Vorinostat prevents cancer cells from dividing and promotes cell death. The Food and Drug Administration approved vorinostat in October, 2006. Vorinostat is marketed as Zolinza by Merck. It is classified as an orphan drug because of the rarity of CTCL.

A T cell is dividing as seen under a microscope (magnification 1000x). Cutaneous T cell lymphoma results from uncontrolled T cell division and acculmation in the skin. Vorinostat prevents T cells from dividing. Source: Wikimedia Commons

Other Names

Vorinostat is also called suberoyl anilide hydroxamic acid (SAHA).

Uses

Vorinostat is used to treat adults with CTCL. CTCL is a form of lymphoma in which the T cells of the immune system grow and collect in the skin. Vorinostat is used when the CTCL gets worse, does not go away, or comes back after treatment with other medicines.

How Vorinostat is Taken

Vorinostat is sold as 100 mg capsules. The recommended dose is 400 mg once daily. The dose can be reduced to 300 mg once daily, or 300 mg once daily for five consecutive days each week, if the 400 mg dose is not well-tolerated. The drug is typically taken with a meal because food can increase its absorption into the body.

How Vorinostat Works

The DNA in cells is wrapped around proteins called histones. The enzyme histone deacetylase deactivates histones, which prevents DNA from creating proteins. Some cancer cells survive and proliferate because they contain and overabundance of histone deacetylase. Vorinostat inhibits this enzyme. Consequently, genes begin to overproduce proteins and eventually the cancer cells stop dividing and die.

How the Body Affects Vorinostat

Vorinostat reaches a peak concentration in the blood approximately four hours after a 400 mg dose. Vorinostat is metabolized through various chemical processes by enzymes in the liver. About half of a dose of vorinostat is excreted in the urine. The half-life of vorinostat, or time needed for the concentration of the drug in the blood to be reduced by half, is approximately two hours.

Side Effects

Below are some of the more common side effects of vorinostat:

• gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, constipation)
• constitutional symptoms (fatigue, chills)
• blood abnormalities (low platelets, low red blood cell count (anemia))
• taste disorders (bad taste in the mouth, dry mouth).

The most serious side effects are pulmonary embolism and anemia (see “Risks and Precautions”).

Risks and Precautions

The greatest risks associated with the use of vorinostat involve the lungs and blood. Pulmonary embolisms (a blood clot that lodges into veins in the lungs) and deep vein thrombosis (a blood clot in the leg veins) have been reported in patients treated with Vorinostat. Vorinostat has also been reported to suppress the production of both platelets and red blood cells or hemoglobin. A low platelet number is called thrombocytopenia, and deficiencies in the latter result in anemia. Thrombocytopenia and anemia are more likely to occur with high doses.

Vorinostat may increase blood sugar levels (hyperglycemia). Diet or some medicines can help keep blood sugar levels within a normal range.

The effect of vorinostat on human fetal development is not known. However, animal studies have shown that vorinostat crosses the placenta and enters fetal blood. This resulted in abnormal development of the fetus, such as reduced fetal weight and incomplete bone formation of the skull, vertebra and other skeletal structures. Thus, the use of vorinostat may represent some risk to a pregnancy.

Drug Interactions

Vorinostat has been reported to increase the effectiveness of anticoagulants like warfarin. Doctors can monitor patients receiving this combination to reduce the risk of excessive bleeding.

The combination of vorinostat with another drug that inhibits histone deacetylase, such as valproic acid(Depakene), increases the risk of gastrointestinal bleeding and low platelet levels.

Clinical Trials

The effectiveness of vorinostat for the treatment of CTCL was assessed in two clinical trials. ^[1]

• In the first study, 74 patients with advanced CTCL were treated with vorinostat at a dose of 400 mg once daily. Effectiveness was measured by response rates in patients with advanced CTCL who had progressive, persistent, or recurrent disease despite treatment with two other medicines. The overall response rate was 30%, and half the patients responded in 55 days or less.

• In the second study, the effectiveness of vorinostat was assessed in 33 patients who did not respond to, or who could not tolerate, at least one other treatment. This study had three treatment groups, or cohorts: cohort 11, 400 mg once daily; cohort 2, 300 mg twice daily for 3 days per week; or cohort 3, 300 mg twice daily for 14 days followed by a 7-day rest. The response rate in the three treatment groups combined was 24%. The response rates were 31%, 9% and 33% in cohort 1, cohort 2 and cohort 3, respectively. The 300 mg twice daily regimen had a higher toxicity with no additional benefits over the 400 mg once daily regimen. Overall, more than half the patients responded in 106 days or less.

References

1. ↑ Zolina Web site. Zolina Product Information. PDF

External Links

Zolinza Home Page

FDA Appoves New Drug for Skin Cancer, Zolinza

FDA Patient Information Sheet: Vorinostat (marketed as Zolinza)

Chemocare.com: Zolinza

RxList: Zolinza