PK of Tenofovir, Emtricitabine and Efavirenz in Healthy Volunteers
Information source: St Stephens Aids Trust
Information obtained from ClinicalTrials.gov on October 04, 2010
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: HIV Infection; HIV Infections
Intervention: Atripla® (Drug)
Phase: Phase 1
Sponsored by: St Stephens Aids Trust
Official(s) and/or principal investigator(s):
Marta Boffito, Dr, Principal Investigator, Affiliation: St Stephen's AIDS Trust
Marta Boffito, Dr, Phone: 0208 846 6507, Email: email@example.com
The purpose of the study is to look at the levels of three HIV medications: tenofovir,
emtricitabine, and efavirenz in blood after the drug intake has been stopped in order to
understand how long these drugs persist in the blood. The study will specifically look at
blood levels of these three drugs (taken as a 3-in-1 tablet) after taking them every day for
This study is not randomised which means that all subjects will receive all study
medications in the same order. You and the study doctor will know which study medications
you are taking at all times during the study.
Official title: Pharmacokinetics of Tenofovir and Tenofovir-diphosphate, Emtricitabine and Emtricitabine-triphosphate, and Efavirenz Once Daily Over 10 Days Following Drug Intake Cessation in Healthy Volunteers
Study design: Control: Uncontrolled, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: pharmacokinetics of plasma tenofovir, emtricitabine and efavirenz
inter subject variability
safety and tolerability of Atripla®
The administration of combination antiretroviral therapy (cART) to HIV-infected patients has
been associated with a dramatic reduction in AIDS-related morbidity and mortality [1-3].
The key to successful HIV drug treatment is adhering to the prescribed combination every day
. The approval of Atripla® (tenofovir/emtricitabine/efavirenz co-formulated in a single
tablet) provides HIV care providers with a "one tablet once a day" therapy, making adherence
much easier for patients.
However, in HIV therapy, successful adherence also means attention to intervals between
doses or dietary restrictions. Ideally, to guarantee long-term virological response,
HIV-infected patients should take their cART every day at the same time. However, cART is
for life and doses can be forgotten or delayed.
Importantly, the 24-week 'Five-on-Two-off' (FOTO) study results were presented in November
2008; these showed that when HIV-infected patients stable (viral load < 50 copies/mL) on
Atripla® were randomised to continue treatment daily or to stop taking it at weekends, no
difference in maintenance of undetectable viral load was observed. Eighty percent in the
control arm and 83% in the 'weekend off' arm had a viral load < 50 copies/mL . This
suggests that either the drugs' effects, or the drugs themselves, persist for a significant
time following drug intake cessation. However, the persistence time and the inter-individual
variability of this parameter for the components of Atripla® have not been clearly defined.
A drug's persistence in plasma or in cells depends on its half life. Long half-life
antiretroviral agents may allow for missed or delayed doses, if concentrations are
maintained at therapeutic levels until the next dose is taken. NRTI are pro-drugs and must
be activated by different phosphorilation steps to be effective against HIV. Intracellular
triphosphate (TP) metabolites have been shown to be characterized by long half lives.
However, data on drug persistence are limited and whether drug doses can be omitted and
dosing delayed is unknown.
Knowledge of the length of time the drug contained in the Atripla® formulation lasts would
increase the confidence of doctors in this combination.
Importantly, triple regimen persistence should be investigated in order to provide
information on the permissiveness (of forgotten or delayed doses) of the whole regimen
rather than one single agent. Due to the simplicity of administering Atripla®, a study
investigating the pharmacokinetic "forgiveness" of tenofovir and emtricitabine (in plasma
and intracellularly) and plasma efavirenz would be readily performed in healthy volunteers
and would provide information on how to advise HIV infected patients on delayed and missed
Rationale for the pharmacogenomics 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. Prospective genetic studies would need to be
planned based on these preliminary data.
Minimum age: 18 Years.
Maximum age: 65 Years.
Subjects must meet all of the following inclusion criteria within 28 days prior to the
1. The ability to understand and sign a written informed consent form, prior to
participation in any screening procedures and must be willing to comply with all
2. Male or non-pregnant, non-lactating females
3. Between 18 to 65 years, inclusive
4. Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive.
5. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for a period of at least 12
weeks after the study
6. Willing to consent to their personal details being entered onto The Over volunteering
Prevention Scheme (TOPS) database
7. Willing to provide photographic identification at each visit.
8. Registered with a GP in the UK
Subjects who meet any of the following exclusion criteria are not to be enrolled in this
1. Any significant acute or chronic medical illness
2. Evidence of organ dysfunction or any clinically significant deviation from normal in
physical examination, vital signs, ECG or clinical laboratory determinations
3. Positive blood screen for hepatitis B surface antigen and/or C antibodies
4. Positive blood screen for HIV-1 and/or 2 antibodies
5. Current or recent (within 3 months) gastrointestinal disease
6. Clinically relevant alcohol or drug use (positive urine drug screen) or history of
alcohol or drug use considered by the Investigator to be sufficient to hinder
compliance with treatment, follow-up procedures or evaluation of adverse events.
Smoking is permitted, but tobacco intake should remain consistent throughout the
7. Exposure to any investigational drug or placebo within 3 months of first dose of
8. Use of any other drugs (unless approved by the Investigator), including
over-the-counter medications and herbal preparations, within two weeks prior to first
dose of study drug, unless approved/prescribed by the Principal Investigator as known
not to interact with study drugs.
9. Females of childbearing potential without the use of effective non-hormonal birth
control methods, or not willing to continue practising these birth control methods
for at least 12 weeks after the end of the treatment period
10. Previous allergy to any of the constituents of the pharmaceuticals administered in
Locations and Contacts
Marta Boffito, Dr, Phone: 0208 846 6507, Email: firstname.lastname@example.org
St Stephen's Centre, London SW10 9TH, United Kingdom; Recruiting
Chris Higgs, Phone: 0208 846 6135, Email: email@example.com
Carl Fletcher, Phone: 0208 846 6323, Email: firstname.lastname@example.org
Laura Waters, Dr, Sub-Investigator
St Stephen's AIDS Trust website
Starting date: June 2010
Last updated: August 13, 2010