Clinical Trial Summary
This study will examine the phototoxicity, a reaction to light that is like exaggerated
sunburn, which occurs in people who take medications such as voriconazole, a medication used
to fight fungus. Sunscreens might protect the skin from the reaction. Although phototoxicity
from voriconazole is not completely understood, it may be related to how that medication is
metabolized in the liver by enzymes called cytochrome P450 enzymes-and mainly by one known as
2C19. A way to evaluate phototoxicity is through microarrays, which measure how much each
gene is expressed in cells from tissues such as skin.
Patients ages 8 and older who are scheduled to begin taking or who currently take
voriconazole may be eligible for this study. Also, patients ages 18 to 45 in good health who
have skin tone known as Type 2, which usually burns and tans only slightly following sun
exposure, may be eligible. All patients will visit the Dermatology Clinic. They will complete
two questionnaires, on medical history and medications, as well as the skin response to
sunlight, and donate about 3 teaspoons of blood. Patients who are scheduled to take
voriconazole will visit the clinic four times, that is, two visits 2 consecutive days before
beginning the medication and two visits on 2 consecutive days after taking it for at least 7
days. Each visit will take 1 to 2 hours. Patients about to take voriconazole will have a
blood test and undergo a physical exam of the skin test site, on the buttocks. Researchers
will take photographs of the specific site and do tests to measure skin reaction to
ultraviolet (UV) light. UV light will be shined on 15 small areas of the skin, each 1 x 1
centimeters. After 24 hours, any redness that occurs on the skin will be checked. Afterward,
patients will begin taking voriconazole according to directions by the researchers. At 10 or
more days later, patients will visit the clinic. Sunscreen will be applied and 1 hour later
after administration of voriconazole, a blood sample will be drawn to check the level of
medication. Then UV light will be shined on 23 areas of skin 1 x 1 centimeters. More
photographs will be taken of test sites to record changes in skin redness. On the next day,
the skin response will be evaluated. Participants in the control group will be asked to avoid
UV radiation by wearing hats and clothing, and using sunscreen. They will be given the
doxycycline, an antibiotic, and undergo procedures with UV light shined on small areas of the
skin, on the buttocks. Control participants will have 7 study days, with visits lasting from
1 to 3 hours and probably not exceeding 8 hours. They will have two shave biopsies on Study
Day 2 and on Study Day 7 to determine how the skin has responded to UV light exposures.
Background:
- Phototoxicity is a sunburn-like response associated with certain medications and is a
phenomenon which is not completely understood. Although clinically similar to a typical
sunburn reaction, the gene expression changes in phototoxic skin reactions may differ
from those in typical sunburn.
- Doxycycline is a relatively well-tolerated and known phototoxic antimicrobial which can
be used in healthy volunteers to increase susceptibility to phototoxicity.
- Characterizing potential risk factors to phototoxicity secondary to voriconazole, a
broad-spectrum antifungal agent associated with potentially treatment-limiting
phototoxicity, may allow identification of subjects at risk for the adverse reaction via
pharmacogenetic evaluation and medical record review.
- Subjects at risk of phototoxicity may benefit from application of effective sunscreens.
Objectives:
- To determine the global gene expression profiles in skin exhibiting phototoxic reactions
in healthy volunteers treated with doxycycline, and compare expression profiles in skin
exposed to ultraviolet (UV) radiation occurring in the absence of doxycycline.
- To investigate the effects of the doxycycline alone in the skin of phototoxic and
non-phototoxic healthy volunteers.
- To characterize voriconazole-related phototoxicity reactions in subjects with the use of
phototesting and to determine if these subjects may receive reasonable phototoxic
protection from the use of sunblock.
Eligibility:
- I & II) Healthy volunteers with skin phototype II.
- III) Subjects scheduled to begin voriconazole therapy.
- IV) Subjects on chronic voriconazole with or without a history of phototoxicity
reaction.
- Previously treated healthy volunteers (I & II) who were evaluated to be either
phototoxic
OR non-phototoxic.
Design:
- I) For the Screening visit arm, forty healthy volunteers will undergo screening with
pertinent skin exam and blood work to evaluate ANA/ENA and liver function profile.
- II) For the Study visit arm, eligible healthy volunteers will undergo phototesting and
will have skin biopsies prior to initiating a 3-day course of oral doxycycline 100 mg
twice daily.
- After the last dose of doxycycline, healthy volunteers will undergo on-treatment MED
testing.
- In those demonstrating phototoxicity, skin biopsies will be performed and submitted for
processing for microarray analysis.
- III) Thirty-five subjects scheduled to begin voriconazole will undergo CYP450 genotyping
and baseline phototesting prior to initiation of voriconazole.
- Adult subjects will be invited to undergo optional skin biopsies pre-drug and on-drug.
- Repeat phototesting will be performed in subjects after at least 7 days of voriconazole
to determine if voriconazole predisposes to phototoxicity.
- Subjects with voriconazole phototoxicity will be invited to undergo sunscreen testing.
- IV) Seventy subjects with prior clinical history of voriconazole phototoxicity as well
as known voriconazole phototoxicity non-reactors will undergo CYP450 genotyping and
potential phototesting.
- To investigate the effects of the doxycycline alone in the skin of healthy volunteers
previously categorized as phototoxic and non-phototoxic