Atazanavir/Ritonavir and Darunavir/Ritonavir PK Tail Study
Condition: HIV; HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of the study is to look at the levels of three HIV medications darunavir,
      ritonavir and atazanavir in the blood after the drug intake has been stopped in order to
      understand how long these drugs persist in blood for. The study will specifically look at
      these three drugs blood levels after taking them for 10 days everyday.

      The main objective is to provide information on the potential safety (in terms of preventing
      virological failure and the development of resistance)of delaying drug doses occasionally by
      providing information on the decline in drug concentration after dosing has stopped.
    

Detailed description: 
      The long term use of and success of antiretroviral therapy (ART) is constrained by many
      factors including poor adherence and drug intolerance. Poor adherence (missing ART doses) may
      lead to the achievement of sub therapeutic drug plasma concentrations and virological
      failure. This could also be complicated by the development of resistance to ART which
      compromises future therapeutic options because of cross resistance within antiretroviral drug
      classes.

      In medicine, successful adherence is supposed to mean taking at least 80% of doses. This is a
      concept, which has been inherited from the antihypertensive literature and anti-infective
      prescribing for therapeutic areas which from that of HIV prescribing in fundamental
      principles. The current absence of a curative therapy for HIV infection, means that in order
      to be effective, suppressive therapies need to be taken on an indefinite lifelong basis. The
      capacity for development of resistance of the virus means that successful adherence equates
      to a much higher rate of adherence than 80%. Moreover, in HIV therapy, successful adherence
      also means attention to a maximum interval between doses as well as dietary restriction at
      the time of dose intake.

      Ideally, to guarantee long-term virological response, HIV-infected patients should take their
      ART every day at the same time. However, ART is for life and doses can be forgotten or
      delayed.

      A recent survey confirmed the reasons why people miss their antiretroviral doses: they
      forget, they fall asleep, they are too busy, they are depressed, they are away from home, and
      their medicines make them sick (Mascolini www.thebody.com 2003).

      Drug persistence (the presence of drug at a detectable level high enough to work) in plasma
      mainly depends on the half-life. Long half-life antiretroviral agents may allow for forgotten
      doses, if they are able to delay the decline of the drug level to sub-therapeutic
      concentrations for long enough for the patient to remember to take the drug. Boosted PI are
      characterized by different half lives, and therefore different abilities to persist in
      plasma.

      Unfortunately, data on drug persistence in plasma are limited and whether drug doses can be
      forgotten and dosing delayed is unknown.

      Therefore, the main objective of this study is to provide information on the potential safety
      (in terms of preventing virological failure and the development of resistance) of delaying
      drug doses occasionally by providing information on the decline in drug concentration after
      dosing has stopped.

      Rationale for pharmacogenomic analysis

      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 associations. Prospective genetic studies would need
      to be planned based on these preliminary data.
    

Intervention name(s): darunavir/ritonavir then atazanavir/ritonavir
Intervention type(s): Drug
Intervention description(s): Phase 1: Oral darunavir/ritonavir 800/100 mg once daily for 10 days
Phase 2: Oral atazanavir/ritonavir 300/100 mg once daily for 10 days
Other intervention name(s): Prezista = TMC114; Norvir,; Reyataz = BMS-232632
Intervention MeSH terms: Ritonavir; Atazanavir Sulfate; Darunavir
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment