Abacavir Pharmacokinetic Study in the Absence/Presence of Darunavir/Ritonavir or Raltegravir in HIV-infected Subjects
Condition: HIV
Study type: Interventional
Phase: Phase 1

Summary: 
      The study is being conducted as we have found that many patients with Human Immunodeficiency
      Disease (HIV) require a combination of different drugs to treat the HIV infection. Before
      using different combination of drugs, it is important to do studies to see if the drugs will
      affect the activity of one another.

      The study aims to help us understand if darunavir/ritonavir or raltegravir have any effects
      on levels of abacavir in the blood.

      The purpose of the study is to assess the pharmacokinetics (how a drug is absorbed,
      distributed and eliminated from your body) of abacavir in the absence and in the presence of
      darunavir/ritonavir and raltegravir.
    

Detailed description: 
      Since the co-administration of nucleoside analogues and protease inhibitors, and soon
      integrase inhibitors, forms an integral part of highly active antiretroviral therapy (HAART)
      and these combinations may result in unexpected drug interactions (as demonstrated by
      interactions between protease inhibitors and TFV), it is therefore important to elucidate the
      impact of ARV co-administration on drug levels.

      The risk of ABC hypersensitivity (HSR) precludes the study of this agent in healthy
      volunteers therefore this study will be performed in HIV-infected subjects. Clinical efficacy
      of drugs is related to their plasma concentrations [Boffito, 2005] and it is important to
      know whether ABC has any impact on the levels of therapeutic agents that may impact on their
      clinical efficacy. Moreover, it is still unknown whether ABC exposure is altered by the
      ritonavir-boosted protease inhibitors darunavir or by the new HIV drug raltegravir.
      Raltegravir will be soon approved for the treatment of HIV in Europe and United States.

      Pharmacogenetics holds promise in HIV treatment because of the complexity and potential
      toxicity of multi antiretroviral drug therapies that are prescribed for long periods. Thus
      far, few candidate genes have been examined for a limited number of allelic variants, but a
      number of confirmed associations have already emerged.

      From a public health perspective, as antiretroviral medications become increasingly available
      to racially and ethnically diverse populations worldwide, understanding the genetic
      structures of each population may allow us to anticipate the impact of adverse responses,
      even in groups that were not represented in drug registration trials.

      The existing literature on pharmacogenetic determinants of antiretroviral drug exposure, drug
      toxicity, as well as genetic markers associated with the rate of disease progression
      underline the recent advances which occurred in the past few years.

      However, it is expected that larger-scale comprehensive genome approaches will profoundly
      change the landscape of knowledge in the future. Additional studies are needed to assess the
      implications for long-term responses to antiretroviral agents.

      For this reason we plan to collect a single blood sample from each participant in our
      intensive pharmacokinetic studies, such as this one, in order to be able to investigate the
      association between genetic polymorphisms in drug disposition genes (such as those encoding
      for cytochrome P450 isoenzymes or transmembrane transporters) and drug exposure. A candidate
      gene approach will be utilised to examine loci of interest. This procedure will provide
      potentially important information on genetic influences on plasma drug concentrations and
      give insight into how to improve the management of HIV-infected patients by individualising
      therapy. These studies will not be powered for genetic associations but will enable us to
      build a data base of genotype-phenotype. Prospective genetic studies would need to be planned
      based on these preliminary data.
    

Intervention name(s): Abacavir; Darunavir/ritonavir; Raltegravir
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Group 1 will be instructed to take • Abacavir 600 mg once daily (two 300 mg tablets once daily) as part of regular treatment throughout the whole study
Group 2 will be instructed to take
• Abacavir 600 mg once daily (two 300 mg tablets once daily) as part of regular treatment throughout the whole study; Group 1 will be instructed to take
• Three 300mg Darunavir tablets and one 100mg ritonavir tablet once a day for 14 days (on days 2 - 15); Group 1 will be instructed to take • Two 200mg Raltegravir tablets twice daily for 14 days (on 16 - 29)
Group 2 will be instructed to take
• Two 200mg Raltegravir tablets twice daily for 14 days (on days 2-15)
Other intervention name(s): Ziagen®; Trizivir®; Kivexa®.
Intervention MeSH terms: Ritonavir; Darunavir; Raltegravir Potassium; Abacavir
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment