A Pilot of Pediatric/Adult Study of Gene Expression Profiling and Clinical Characterization of Phototoxicity
Condition: Healthy Volunteers; Fungal Infections; Bacterial Infections
MeSH terms: Infections; Communicable Diseases; Bacterial Infections; Mycoses; Dermatitis, Phototoxic
Study type: Interventional
Phase: Phase 1

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.

      ...
    

Detailed description: 
      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
    

Intervention name(s): Doxycycline; Voriconazole
Intervention type(s): Drug; Drug
Intervention description(s): 100mg twice daily for 3 days. Two hours after the last dose of doxycycline is taken in the clinic, on-medication phototesting with ssUVR, UVA, and visible light will be performed.; After taking voriconazole for (Bullet)7 days to achieve a steady state of voriconazole for subjects, on-medication phototesting with ssUVR, UVA, and visible light will be performed.
Intervention MeSH terms: Doxycycline; Voriconazole
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Phototesting; UVR/UVA; Sunburn; Doxycycline; Voriconazole