Helping patients feel good in their own skin
Focus on Dermatology
Although skin is the largest organ of the human body, dermatologic disorders do not necessarily receive the attention they deserve. Treating dermatological problems may not be as simple as it seems. Fortunately, pharmacists now have at their fingertips new therapies for dermatologic diseases, including melanoma, and topical and transdermal formulations that will increase the utility of currently available medications.
Skin cancer treatments
One of the most serious dermatologic diagnoses, skin cancer can range from more prevalent types—basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)—to more aggressive cancers such as metastatic melanoma.
“Melanoma is the deadliest form of skin cancer because it can metastasize throughout the entire body, even when the skin lesion is smaller than a grain of rice,” said Tobias Schatton, PharmD, PhD, Instructor at Harvard Medical School and Research Associate at Brigham and Women’s Hospital in Boston. “BCC and SCC are not very lethal and do not metastasize extensively or frequently, but when they do, they are difficult to treat. For decades, metastatic melanoma was considered an automatic death sentence, but now, thanks to evolving therapies, there is hope for many patients.”
The best treatment for all skin cancers, especially melanoma, is early detection and surgery. Once the cancer metastasizes, survival rates are substantially reduced. However, when surgery is no longer an option, patients and clinicians can choose from several approaches for treating the cancer. Cytotoxic chemotherapy with agents such as dacarbazine can be used, but it has not been shown to improve overall survival of patients with malignant melanoma.
Another option is an immunotherapy. High-dose interleukin-2 (IL-2) and “immune checkpoint blockers” activate immune responses that trigger cytotoxic T cells to attack the cancer cells. The first immune checkpoint blocker approved by FDA was ipilumumab (Yervoy—Bristol-Myers Squibb), a monoclonal antibody that binds to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4). In clinical trials, ipilimumab improved overall survival of patients with metastatic melanoma for about 4 to 5 months. “One problem with therapies targeting CTLA-4 is that this checkpoint regulates a multitude of physiologic immune components, and disruption of these pathways can cause patients to experience severe immune-related side effects,” Schatton said. In a recent Phase III clinical trial by Antoni Ribas, MD, and colleagues that was published in the Journal of Clinical Oncology, a newer anti–CTLA-4 antibody, tremelimumab, failed to demonstrate a survival benefit compared with dacarbazine.
Other types of treatments for melanoma target oncogenic pathways such as the BRAF pathway, which promotes cell proliferation and prevents apoptosis by activating the mitogen-activated protein kinase (MAPK) pathway. Inhibitors developed to specifically block the mutant BRAF (V600E) variant include vemurafenib (Zelboraf—Genentech, Roche); patients with this or other BRAF-activating mutations showed an initial response to therapy, but frequently developed treatment resistance later on. “While many patients show remarkable response to BRAF inhibition, most patients experience relapse within a year,” Schatton said. Another BRAF kinase inhibitor, dabrafenib (Tafinlar—GlaxoSmithKline) received FDA approval in 2013.
“[Mitogen-activated extracellular kinase (MEK)] inhibitors such as trametinib [Mekinist—GlaxoSmithKline] are another class of drugs used for the treatment of BRAF mutant melanomas [that] have demonstrated similar clinical activity,” Schatton said. Trametinib is the first MEK inhibitor approved by FDA for treatment of metastatic melanoma in patients with BRAF V600E or BRAF V600K mutations. It can be used as a monotherapy or in combination with dabrafenib. “The combination of MEK and BRAF inhibitors was found to increase life expectancy more effectively than monotherapy,” Schatton said. Another MEK inhibitor, selumetinib, is being investigated for metastatic melanoma of the eye.
“Very promising types of immune checkpoint blockers are anti–PD-L1 [anti-programmed cell death 1 ligand 1] and anti–PD-1 [programmed cell death 1] antibodies,” Schatton added. These antibodies bind to the respective ligand or protein on the surface of exhausted T cells and cause these T cells to launch an immune attack on the cancer. “More than 30% of patients with melanoma showed promising clinical response to PD-1 pathway inhibition,” he said. Anti–PD-1 antibodies such as nivolumab and lambrolizumab are being investigated, as well as potentially synergistic combinations of anti–PD-L1 or anti–PD-1 with ipilimumab, BRAF inhibitors, or MEK inhibitors. However, one study of a combination of vemurafenib and ipilimumab showed an increased level of hepatotoxicity; liver enzyme monitoring may be required with these drugs.
Exposure to ultraviolet (UV) light, both outdoors and indoors, is the most prominent cause of BCC, SCC, and melanoma, and daily sunscreen use can decrease the incidence of melanoma by one-half, according to the American Association for Cancer Research’s Cancer Progress Report 2013 in Clinical Cancer Research.
Indoor tanning, commonly from tanning beds, is causally related to the incidence of melanoma and is causing a steep rise in melanoma incidence among young women. Currently California, Illinois, Nevada, Texas, and Vermont ban the use of tanning beds for all minors younger than 18 years, and at least 33 states and the District of Columbia regulate the use of tanning facilities by minors, according to the National Conference of State Legislatures.
“Melanoma is a common cancer that can affect people of any race, age, or gender,” Schatton said. As early detection and monitoring are important for reducing melanoma-related fatalities, pharmacists should encourage all patients to seek regular skin screenings by their physician.
Five new products on the market
In November 2013, FDA approved a topical formulation, mechlorethamine hydrochloride gel 0.02% (Valchlor 0.016%—Ceptaris Therapeutics), for the treatment of Stage IA/IB mycosis fungoides–type cutaneous T-cell lymphoma in patients who have received a prior skin-directed therapy.
A new antifungal drug, luliconazole (Luzu Cream 1%—Valeant Pharmaceuticals), was approved by FDA in November for marketing as a topical cream approved to treat athlete’s foot (interdigital tinea pedis), jock itch (tinea cruris), and ringworm (tinea corporis) caused by Trichophyton rubrum and Epidermophyton floccosum in patients aged 18 years and older. Depending on the indication, the cream is applied once daily for either 1 or 2 weeks.
Polidocanol (Varithena—BTG plc) is a newly FDA-approved sclerosing agent prepared in a foam for I.V. administration and with ultrasound guidance only by a health care provider. It is indicated for the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the great saphenous vein system above and below the knee.
Acyclovir tablets for buccal administration (Sitavig—BioAlliance Pharma) have been approved by FDA to treat recurrent cold sores (herpes labialis) in immunocompetent patients. The 50-mg tablet is applied as a single dose in the upper gum region and held in place for 30 seconds to ensure adhesion. The tablet should be applied within 1 hour after the onset of symptoms and before the appearance of any signs of herpetic lesions.
A vasoconstrictor commonly given as an ophthalmic drop for glaucoma, brimonidine gel (Mirvaso—Galderma Labs), has been approved by FDA for treating persistent and nontransient facial erythema of rosacea in adults aged 18 years or older. A pea-size amount of the gel should be applied once daily to the central forehead, chin, nose, and each cheek.
“One of the recent directions in dermatology includes developing novel dermatology products for topical or transdermal delivery, especially for more specialized populations such as pediatrics or geriatrics,” said Nicole Brogden, PharmD, PhD, Associate in the Department of Pharmaceutical Sciences and Experimental Therapeutics at the University of Iowa College of Pharmacy. “Patient adherence and satisfaction have been shown to increase with cutaneous delivery, and these products have unique therapy outcomes that other delivery methods do not provide.”
Topical delivery can reduce unwanted systemic effects of the drug, while transdermal therapy delivers a drug systematically without repeated oral or I.V. dosing. One recent example of a transdermal product is the microneedle technology of the intradermal flu vaccine (Fluzone Intradermal—Sanofi Pasteur).
Brogden’s research focuses on developing a minimally invasive delivery technology and alternate ways to administer drugs transdermally, including the delivery of analgesic drugs for osteoarthritis using microneedle technology (each needle is only 750 µm in length, about 50% larger than the period at the end of this sentence). For the pediatric population and adults with needle phobia, administering drugs I.V. or I.M. can be a major clinical challenge. Transdermal therapy “is simpler for geriatric patients and for caregivers, and is often preferred,” Brogden said.
“Skin is a very dynamic organ and it changes over [a] lifetime, so we have to think about patient populations differently when we develop a new product or treatment,” Brogden said. Formulating medications so that patients can adhere to the regimen for long-term therapy is critical. But making such products is no walk in the park. “There are challenges to formulating drugs for delivery through the skin. Some of the drugs are very large molecules, which can make them very difficult to formulate into a topical or transdermal delivery system,” she said. “Sometimes we see these products failing in clinical trials because patients didn’t really understand how to use them appropriately.”