Pharmacokinetics (PK) Study of Once Daily Darunavir/Ritonavir and Twice and Once Daily Raltegravir in HIV-infected Subjects
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      The study aims to help us understand if the HIV drugs darunavir (taken with ritonavir) and
      raltegravir will affect each other when they are given at the same time.

      The purpose of the study is to assess the pharmacokinetics (how a drug is absorbed,
      distributed and eliminated from your body) of darunavir and ritonavir when these are taken
      with and without raltegravir.

      The duration of the study will be up to 50 days plus a screening visit which will take place
      up to 4 weeks prior to the start of the study, and a follow up visit which takes place 1-2
      weeks after the last dose of study medication.

      Subjects will continue to take 2 of their usual drugs (those called nucleoside reverse
      transcriptase inhibitors -NRTI) throughout the study.

      For the first 21 days subjects will take their usual NRTI plus raltegravir 400mg twice daily.
      After this, subjects will also receive either:

      Group 1) Darunavir/ritonavir 800mg/100mg once daily AND raltegravir 400mg twice daily or
      Group 2) Darunavir/ritonavir 800mg/100mg once daily AND raltegravir 800mg once daily

      Subjects will take this regimen for 14 days. Subjects will be randomly allocated to either
      Group 1 or 2. You will have an equal (50/50) chance of being allocated to Group 1 or 2.
    

Detailed description: 
      The integrase inhibitor raltegravir has shown to a potent new agent for the treatment of HIV
      infection.

      When raltegravir and darunavir/ritonavir have been combined in the Benchmark studies, they
      provided an excellent virological response in highly experienced patients.

      Darunavir once daily use is increasing due to patients' preference for once daily regimens.

      Raltegravir has not shown any pharmacokinetic/pharmacodynamic relationship and doses of 100
      to 400 mg twice daily have shown similar virological responses. This may be due to
      intracellular drug accumulation.

      However, data on the use of darunavir/r plus raltegravir once daily and on raltegravir
      intracellular concentrations are not available.

      Whether raltegravir is efficacious when administered once daily is unknown. However,
      concentrations higher the IC95 of 33nM have been associated to a favourable virological
      response.

      Therefore, we would like to investigate the plasma and intracellular pharmacokinetics of
      darunavir/ritonavir and raltegravir when co-administered once daily in order to provide
      further data to support the use of these agents once daily, patients' preferred dosing
      schedule.

      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): Raltegravir plus Darunavir/ritonavir; Raltegravir plus Darunavir/ritonavir
Intervention type(s): Drug; Drug
Intervention description(s): Phase 1, all subjects (n = 24): Raltegravir 400 mg twice daily for 21 days
Phase 2 Group 1 (n = 12): Darunavir/ritonavir 800/100 mg once daily plus raltegravir 400 mg twice daily for 14 days
Phase 3, all subjects (n = 24): Darunavir/ritonavir 800/100 mg once daily for 14 days.; Phase 1, all subjects (n = 24): Raltegravir 400 mg twice daily for 21 days
Phase 2
Group 2 (n = 12): Darunavir/ritonavir 800/100 mg once daily plus raltegravir 800 mg once daily for 14 days
Phase 3, all subjects (n = 24): Darunavir/ritonavir 800/100 mg once daily for 14 days.
Other intervention name(s): darunavir = TMC114; ritonavir = Norvir trade name; raltegravir = MK-0518, brand name Isentress; darunavir = TMC114; ritonavir = Norvir trade name; raltegravir = MK-0518, brand name Isentress
Intervention MeSH terms: Ritonavir; Darunavir; Raltegravir Potassium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment