Atazanavir/Ritonavir and Darunavir/Ritonavir PK Tail Study
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.
Drug: darunavir/ritonavir then atazanavir/ritonavir
|Study Design:||Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pharmacokinetics of Darunavir/Ritonavir Once Daily and Atazanavir/Ritonavir Once Daily Over 72 Hours Following Drug Intake Cessation|
- Pharmacokinetics [ Time Frame: 30 days (excluding screening and follow-up) ] [ Designated as safety issue: No ]To assess the pharmacokinetics of darunavir/ritonavir once daily and atazanavir/ritonavir once daily over 72 hours following drug intake cessation
- Inter-Subject Variability [ Time Frame: 30 days ] [ Designated as safety issue: No ]To assess the inter subject variability in darunavir and atazanavir plasma concentrations over 72 hours following drug intake cessation.
- Safety and Tolerability [ Time Frame: 30 day (excluding screening and follow up) ] [ Designated as safety issue: Yes ]To assess the safety and tolerability of darunavir/ritonavir and atazanavir/ritonavir over 10 days of administration
- Pharmacogenetics [ Time Frame: 30 day (excluding screening and follow up) ] [ Designated as safety issue: No ]To investigate the association between genetic polymorphisms in drug disposition genes and drug exposure
|Study Start Date:||April 2010|
|Study Completion Date:||June 2010|
|Primary Completion Date:||June 2010 (Final data collection date for primary outcome measure)|
All Subjects will receive the same intervention
Drug: darunavir/ritonavir then atazanavir/ritonavir
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
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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.