Pharmacology Update
Vorinostat Capsules (Zolinza™)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.
A new class of drug has been approved for the treatment of cutaneous T-cell lymphoma (CTCL) such as mycosis fungoides. Vorinostat is an orally active histone deacetylase (HDAC) inhibitor. It is manufactured by Pantheon, Inc in Canada and marketed by Merck & Co as Zolinza.
Indications
Vorinostat is indicated for the treatment of cutaneous manifestation of T-cell lymphoma in patients who have progressive, persistent or recurrent disease on or following two systemic therapies.1
Dosage
The recommended dose is 400 mg once daily with food. Patients should drink at least 2 liters of fluid daily to avoid dehydration while taking vorinostat. Treatment may be continued until the disease progresses or the development of unacceptable toxicity. If the 400 mg dose is not tolerated the dose may be reduced to 300 mg once daily.1
Vorinostat is available as 100 mg capsules.
Potential Advantages
Vorinostat is the first HDAC inhibitor approved for CTCL providing a drug with a different mechanism of action for patients refractory to, or intolerant of, current therapy.
Potential Disadvantages
Common (> 20%) adverse events include increased serum glucose (69%), fatigue (52%), diarrhea (52%), proteinuria (51%), transient increase in serum creatinine (47%), nausea (41%), dysgeusia (28%), thrombocytopenia (26%), anorexia (24%), and weight loss (21%). Serious adverse events include pulmonary embolism (4.7%), squamous cell carcinoma (3.5%), and anemia (2.3%). Prolongation of QTc has also been reported. Vorinostat may be harmful to the fetus. Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of vorinostat and other HDAC inhibitors such as valproic acid. Concomitant administration of vorinostat and warfarin can prolong prothrombin time and increase INR value.1
Comments
Vorinostat is an HDAC inhibitor. Histone deacetylases catalyzes the removal of acetyl groups from lysine residues of proteins (eg, histones). Overexpression of HDAC is observed in certain cancers. The accumulation of excess acetylated histones leads to cell death. The expedited approval of the drug was based on 2 open-label studies, one involving 74 patients with advanced CTCL who had progression, persistence, or recurrence on or following 2 systemic therapies. They were also intolerant to or not a candidate for bexarotene. All patients received vorinostat 400 mg daily. Efficacy was evaluated as complete clinical response (ie, no evidence of disease) or partial response (50% improvement in the disease). Complete or partial response needed to be maintained for 4 weeks. Overall all response was 29.5% with one complete response. Median times to response were 55 days. It may take up to 6 months in rare cases. In the second study (n = 33), 28 patients had advanced CTCL and were assigned to receive 400 mg daily, 300 mg twice daily for 3 days/week, or 300 mg daily for 14 days each 21 days. Response rates were 30.8%, 9.1%, and 33.3%. The estimated duration of response ranged from 84-168 days and time to disease progression, 202-211 days. The 300 mg twice-daily dose was associated with greater toxicity. Dose-related thrombocytopenia and anemia have been reported. Adverse events led to discontinuation of therapy in 9.3% of patients and 10.5% required dose modification after receiving 400 mg daily dosing. The median time to first adverse events was 42 days (17-253 days). Monitoring of blood cell counts, electrolytes, glucose, and serum creatinine should be done every 2 weeks for the first 2 months of therapy and monthly thereafter.1 The 30-day cost is $7200.
Clinical Implications
CTCL is a rare cancer with an annual incidence of 3 per 1 million people.2 The most common (44%) form is mycosis fungoides.3 There is currently no cure for CTCL. Systemic therapy includes chemotherapy, interferon, denileukin diftitox or bexarotene. An overall response of 48% has been reported with bexarotene.4 Vorinostat provides an alternative to those who are intolerant of or not a candidate for bexarotene as well as other therapy.
References
1. Zolinza Product Information. Merck & Co. October 2006.
2. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01484.html. Accessed 4/8/07.
3. http://www.emedicine.com/med/topics3486.htm. Accessed 4/8/07.
4. Apisarnthanarax N, et al. Am J Clin Dermatol. 2002;3:193-215.
A new class of drug has been approved for the treatment of cutaneous T-cell lymphoma (CTCL) such as mycosis fungoides.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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