Influence of the MDR1 Genotype on Blood Levels of Indinavir and Saquinavir in Healthy Volunteers
Condition: Healthy; HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      This study will examine whether a particular type of gene (MDR1) in the body can affect blood
      levels of two protease inhibitors, indinavir and saquinavir, which are used to treat people
      with HIV. If blood levels of these drugs are too low or too high, they may not work well or
      may cause side effects in patients. This study will determine how MDR1 genes might affect
      absorption of these medicines.

      Healthy normal volunteers between 18 and 50 years of age may be eligible for this study.
      Candidates will be screened with a medical history and blood and urine tests. The blood will
      be tested for:

        -  Routine laboratory values for assessing general health

        -  HIV

        -  MDR1 gene type

        -  Amount of P-glycoprotein (a protein made by the MDR1 gene) on T cells.

      Participants will have blood drawn three more times, as follows:

        -  After one dose of the sedative midazolam (Versed(Registered Trademark)): Participants
           will take an 8-milligram dose of midazolam syrup by mouth. Four hours later, a single
           blood sample will be drawn through a needle in an arm vein. This part of the study will
           assess the efficiency of a certain enzyme involved in metabolizing (breaking down)
           indinavir and saquinavir.

        -  After four doses of indinavir: About a week after taking the midazolam, participants
           will take 800 mg of indinavir (two capsules) 3 times a day (every 8 hours) for 1 day.
           The following morning they will come to the clinic, where a catheter (flexible plastic
           tube) will be placed in an arm vein for repeated blood draws. A blood sample will be
           drawn, and a fourth and final dose of indinavir will be given. Seven blood samples of
           about a teaspoon each will then be collected through the catheter over an 8-hour period
           to measure blood levels of the drug.

        -  After 10 doses of saquinavir: About a week after the last dose of indinavir,
           participants will start taking 1,200 mg (6 capsules) of saquinavir soft-gelatin capsules
           3 times a day for 3 days. On the fourth day, participants will come to the clinic. A
           catheter will be inserted into an arm vein and about 4 teaspoons of blood will be
           collected for routine laboratory tests and to measure saquinavir levels. A urine sample
           will also be collected for routine tests. Participants will then receive the tenth and
           final dose of saquinavir, and eight blood samples of about a teaspoon each will be
           collected through the catheter over an 8-hour period.
    

Detailed description: 
      The expression of P-glycoprotein, a transporter protein present in enterocytes as well as
      other cells involved in the absorption and distribution of HIV protease inhibitors, has been
      linked to a single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T.
      Individuals homozygous for the T allele have reduced P-gp expression compared to CC
      individuals. Preliminary studies by other investigators to determine the influence of MDR1
      genotype on HIV protease inhibitor pharmacokinetics have yielded inconclusive results. The
      primary purpose of this study is to determine the relationship, if any, between MDR1
      genotypes and plasma concentrations of the HIV protease inhibitors indinavir and saquinavir.
      Secondary objectives of this investigation will (1) assess the relationship between CYP3A4
      activity and indinavir and saquinavir exposure and (2) characterize the relationship, if any,
      between P-gp expression on lymphocyte surfaces and MDR1 genotype. Up to 150 subjects will be
      screened to enroll a total of 63 healthy volunteers (21 subjects each in the CC, TT, and CT
      groups). Each subject will have blood drawn for P-gp expression analysis and MDR1 genotyping
      at screening. Next, subjects will receive oral midazolam 8 mg for CYP3A4 phenotyping; a
      single blood sample will be collected 4 hours after midazolam administration for
      determination of midazolam and 1-hydroxymidazolam. Between 7 and 28 days after midazolam
      administration, subjects will receive indinavir 800 mg every 8 hours for one day and a single
      800 mg dose the next morning (dose #4). Between 7 and 28 days after indinavir administration,
      subjects will receive saquinavir soft-gel capsules 1200 mg three times daily for 3 days and a
      single dose on the morning of day 4 (dose # 10). Post-dose blood samples will be collected
      over 8 hours following dose #4 of indinavir and dose #10 of saquinavir. Indinavir and
      saquinavir pharmacokinetic parameters (primarily AUC and Cmax) will be compared across MDR1
      genotype groups using ANOVA with post-hoc testing. 1-hydroxymidazolam: midazolam ratios will
      be correlated to indinavir and saquinavir AUCs as well as compared across MDR1 genotype
      groups. P-gp expression on lymphocyte surfaces will be determined by flow cytometry,
      quantified, and compared across MDR1 genotype groups. Data from this investigation will
      determine whether MDR1 genotype influences protease inhibitor plasma concentrations.
    

Intervention name(s): Midazolam; Indinavir; Saquinavir
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Indinavir; Saquinavir; Midazolam
Primary purpose: Treatment
Keywords: P-Glycoprotein; Protease Inhibitor; Antiretrovirals; Cytochrome P450; Drug Transporters; Healthy Volunteer; HV