Effect of Genetics on Metabolism of Efavirenz
Condition: Metabolism
Study type: Interventional
Phase: Phase 4

Summary: 
      This study will evaluate the effects of genetics on metabolism of the anti-HIV medicine
      efavirenz (Sustiva) and will see if Efavirenz interacts with bupropion (Zyban or Wellbutrin),
      a drug commonly used to treat depression and to help people quit smoking. Efavirenz is
      metabolized by an enzyme called CYP2B6, which is thought to be more active in some people
      than in others, depending on their genetic makeup. The rate of metabolism of the drug can
      affect how the body responds it and perhaps the ability of the HIV virus to develop
      resistance to it.

      Healthy volunteers between 18 and 55 years of age who are non-smokers and HIV-infected men
      and women 18 years of age and older who are taking efavirenz along with two or three
      nucleoside reverse transcriptase inhibitors may be eligible for this study. Candidates are
      screened with a medical history and physical examination and blood tests, including tests to
      determine which genes they have for four different proteins or enzymes (CYP2B6, CYP3A4,
      CYP3A5, and MDR1) that metabolize drugs.

      Participants are assigned to one of three groups for the following procedures:

      -HIV-infected individuals: Blood samples are drawn to measure efavirenz levels, as follows:
      On the last day of taking efavirenz, the subject skips his or her usual evening efavirenz
      dose the night before sampling. The next morning at clinic, a catheter (flexible plastic
      tube) is inserted into a vein in the subject's arm for collecting blood samples. After the
      first sample is drawn, the subject takes a dose of efavirenz. Eight more blood samples are
      collected at 1, 2, 4, 6, 8, 12, 24 and 48 hours after taking the efavirenz tablet. (The
      catheter is removed after the 12-hour sample and the subject is discharged home, and then
      returns to the clinic for the 24- and 48-hour samples, which are collected through a needle
      inserted into an arm vein.) The subject returns to the clinic four more times for a single
      blood draw at 7, 14, 21 and 28 days after stopping efavirenz.

      HIV-infected patients whose HIV viral load reaches 1,000 copies/L or more within 12 months
      after completing the study are asked to return to the clinic for a blood draw to check the
      genotype of the virus for drug resistance.

        -  Healthy Volunteers - Group 1: Blood samples are drawn to measure efavirenz levels, as
           follows: Participants take one efavirenz tablet once a day for 13 to 15 days. On the
           last day of taking efavirenz, the subject takes his/her last dose of efavirenz in
           clinic, where blood is then collected as described above for HIV-infected individuals.

        -  Healthy Volunteers - Group 2: A catheter is inserted into a vein in the subject's arm
           and a blood sample is drawn through the catheter. The subject then takes a single
           bupropion tablet and additional blood samples are drawn at 1,2, 2.5, 3, 3.5, 4, 6, 8,
           12, 24 and 48 hours after the dose to measure the amount of drug in the blood. Subjects
           begin taking efavirenz 0 to 6 days after the last bupropion blood level is measured. As
           above, subjects will take one efavirenz tablet once a day for 13 to 15 days. On the last
           day of taking efavirenz, a catheter is inserted into the subject's arm. Two blood
           samples are drawn through the catheter, the subject takes the daily dose of efavirenz
           along with a bupropion tablet. Eleven additional blood samples are drawn at 1, 2, 2.5,
           3, 3.5, 4, 6, 8, 12, 24, and 48 hours after taking the pills to measure blood levels of
           bupropion. Eight additional samples are collected at 1, 2, 4, 6, 8, 12, 24, and 48 hours
           to measure efavirenz blood levels. (The catheter is removed after the 12-hour sample and
           the subject is discharged home; the 24- and 48-hour samples are collected through a
           needle inserted into an arm vein.)
    

Detailed description: 
      Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with a long
      half-life, allowing for once-daily dosing. Although it is generally well-tolerated and widely
      used, a major disadvantage of EFV is its relatively low barrier to resistance. The single
      K103N mutation confers high-level resistance to EFV, as well as to all other NNRTI's.
      Acquisition of HIV-1 resistance is likely to result from repeated exposure of the virus to
      subtherapeutic drug concentrations.

      When terminating EFV therapy it is recommended that EFV be stopped 1-2 weeks earlier than
      concomitant antiretrovirals (ARVs) to account for its long washout period. Alternatively,
      substituting EFV with a protease inhibitor for 1 to 4 weeks has also been recommended. Both
      strategies attempt to avoid prolonged EFV exposure following discontinuation of concomitant
      ARVs, thereby lowering the risk of acquiring new resistance mutations. Though widely
      utilized, neither method has been validated by pharmacokinetic or clinical studies. Genetic
      differences in CYP2B6 contribute greatly to observed variability in EFV clearance; hence,
      genetic differences may contribute to significantly different responses to methods of therapy
      discontinuation. Multiple polymorphisms in CYP2B6 have been identified. Substitutions at
      positions 516, 785, and 1459 are the most common variants, and appear to be associated with
      alterations in CYP2B6 activity.

      We propose a 2-part study. Part I is to be conducted in HIV-negative volunteers, and consists
      of: (1) determination of EFV pharmacokinetic (PK) values (following 13-15 days of EFV 600
      mg/day) for comparison between CYP2B6 genotypes (including wild-type and allelic variants at
      positions 516, 785 and 1459), (2) measurement of single EFV plasma concentrations 7, 14, 21,
      and 28 days after the drug is stopped to assess for differences in EFV exposure between
      CYP2B6 genotypes, and (3) comparison of bupropion PK values following administration of a
      single bupropion dose (a) prior to EFV administration and (b) after 13-15 days of EFV, to
      evaluate whether EFV modulates CYP2B6 metabolism using bupropion as a probe for CYP2B6
      function.

      Part II is to be conduced in HIV-positive patients who are planning to discontinue (d/c)
      their EFV therapy, and includes: (1) determination of EFV PK values prior to d/c of therapy
      for comparison between different CYP2B6 genotypes, (2) measurement of single EFV plasma
      concentrations 7, 14, 21 and 28 days post-EFV to assess for differences in exposure across
      CYP2B6 genotypes, and (3) genotypic evaluation of HIV-1 drug resistance performed in any
      patient with an HIV RNA = 1,000 copies/mL, prior to and after EFV discontinuation (up to 12
      months after stopping EFV), as a preliminary study to evaluate the incidence of EFV
      resistance mutations based on CYP2B6 genotype.

      Data from this study will help to describe the relationship between CYP2B6 genetic
      polymorphisms and the PK variability of EFV, specifically addressing the effect on prolonged
      EFV exposure following discontinuation of therapy. In addition, this study will determine
      whether EFV modulates CYP2B6 activity as assessed by bupropion phenotyping. Lastly, it will
      attempt to provide preliminary information about whether genetic variability in CYP2B6 is
      related to the incidence of NNRTI-resistance after stopping or changing EFV therapy.
    

Intervention name(s): Blood draw
Intervention type(s): Procedure
Primary purpose: Treatment
Keywords: Pharmacokinetics; Cytochrome P450; HIV Resistance; Drug Interaction; Non-Nucleoside Reverse Transcriptase Inhibitors; HIV Positive; Healthy Volunteer; HV