Comparison of Concentration-time Course of Plasma and Intracellular Raltegravir in Healthy Volunteers
Condition: Human Immunodeficiency Virus
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      The investigators hypothesize that the concentration-time profile of raltegravir is different
      in cells than that in plasma. Intracellular raltegravir concentrations may be higher and its
      half-life longer than in plasma. This may explain the efficacy of raltegravir despite
      variable plasma concentrations.
    

Detailed description: 
      In less than 15 years, human immunodeficiency virus (HIV) infection has reached the level of
      a pandemic, and acquired immunodeficiency syndrome (AIDS) has been reported in over 190
      countries. By the end of 2001, more than 30 million people were infected with HIV worldwide,
      with approximately one million of those infected residing in North America and one million
      residing in Europe.

      Significant advances have been made in the treatment of HIV disease. The nucleoside reverse
      transcriptase inhibitors provided the earliest therapeutic intervention for HIV infection.
      This class of antiretroviral agents interferes with the replication of HIV by competitive
      inhibition of the HIV reverse transcriptase enzyme and by chain termination of new HIV DNA
      into which the nucleoside analogue has been incorporated. Subsequent development of other
      potent drug classes, such as non nucleoside reverse transcriptase inhibitors and protease
      inhibitors, has made possible the use of multidrug, multiclass regimens that can achieve
      durable suppression of HIV replication. However, extensive resistance has developed to these
      classes of drugs, necessitating the development of other potent classes of antiretroviral
      therapy.

      The integrase inhibitors are a new class of antiretroviral drugs. They inhibit the catalytic
      activity of HIV integrase, an HIV encoded enzyme that is required for viral replication.
      Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated
      linear HIV DNA into the host cell genome preventing the formation of the HIV provirus. The
      provirus is required to direct the production of progeny virus, so inhibiting integration
      prevents propagation of the viral infection.

      Raltegravir (RAL) is a newly approved HIV integrase inhibitor. It is approved in salvage
      regimens(Merck &Co Inc. 2007) and shows promise in first line therapy. Raltegravir is potent
      in vitro; concentrations of 31 ± 20 nM resulted in 95% inhibition (EC95) of viral spread
      (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected
      with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir at concentrations
      of 6 to 50 nM resulted in 95% inhibition of viral spread in cultures of mitogen-activated
      human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of
      HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease
      inhibitors.

      RAL plasma concentrations are highly variable even after controlling for food intake and
      UGT1A1*28 polymorphisms. Despite this variability, RAL remains efficacious and studies have
      shown little correlation between various RAL pharmacokinetic parameters and efficacy(Wenning,
      Hwang et al. 2008). This suggests that although RAL exposure may be important, plasma
      concentrations may not the best marker of RAL exposure.

      RAL exerts its effects in the HIV-infected cells where it inhibits the HIV integrase.
      Therefore intracellular concentrations should correlate with efficacy much more than plasma
      concentrations. It is possible that RAL could accumulate inside HIV-infected cells or that
      intracellular concentrations could be less variable, explaining the sustained efficacy of RAL
      despite variable plasma concentrations. Intracellular half-life could also be longer than the
      relatively short plasma half-life. This information could be used to justify once daily
      administration of RAL, just as zidovudine dosing was changed from five times to twice daily
      because intracellular zidovudine triphosphate had a much longer half-life than plasma
      zidovudine(Barry, Khoo et al. 1996).

      Measurement of intracellular raltegravir could also aid in therapeutic drug monitoring and
      assessing drug-drug interactions. For example, rifampin reduces plasma concentration of RAL
      by almost 50%(Wenning, Hanley et al. 2009). However, dose increases may not be necessary if
      intracellular concentrations are maintained, as is thought to be true for zidovudine after
      rifampin co-administration.

      To our knowledge, there has been no data on intracellular raltegravir. We therefore aim to
      measure the time course of RAL intracellular concentrations after a single dose in healthy
      volunteers.
    

Intervention name(s): Raltegravir
Intervention type(s): Drug
Intervention description(s): One 400mg tablet on day 1.
Other intervention name(s): ISENTRESS, 400mg
Intervention MeSH terms: Raltegravir Potassium
Intervention model: Single Group Assignment
Masking: None (Open Label)
Keywords: HIV