Antiretroviral Drug Interaction Study in Volunteers With HIV
National Institutes of Health Clinical Center (CC)
Information provided by (Responsible Party)
National Institutes of Health Clinical Center (CC)
First received: November 22, 2011
Last updated: June 30, 2017
Last Verified: June 1, 2016
History of Changes
- People who are infected with the human immunodeficiency virus (HIV) are at risk of getting certain diseases. Two of these diseases are a type of pneumonia known as PCP and a brain infection called toxoplasmosis. Most people with HIV take antiretroviral (ARV) drugs to treat HIV and lower the risk of infections. However, some ARV drugs may make other drugs used to treat PCP and toxoplasmosis less effective. Researchers want to test specific ARV drugs to see if they affect atovaquone, a drug used to treat PCP and toxoplasmosis.
- To see if ARV drugs atazanavir-ritonavir or efavirenz lower the blood levels of atovaquone.
- Individuals between 18 and 70 years of age who have HIV.
- Participants must be taking efavirenz or atazanavir-ritonavir, or not taking any ARV drugs.
- Participants will be screened with a physical exam and medical history. They will also have blood and urine tests.
- This study has a screening visit and five study visits. Two of the study visits will last about 12 hours; the other three visits will last about 1 hour each.
- Participants will receive either a low dose or high dose of atovaquone to take for 14 days. They will record doses and any symptoms on a diary card at home.
- After 14 days, participants will have a 12-hour visit to provide blood samples. There will be a wash-out period with no doses for up to 6 weeks.
- After the wash-out period, participants will switch dose levels to either the high or low dose.
Drug : Atovaquone 750 mg twice daily
Drug : Atovaquone 1500 mg twice daily
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||The Influence of Atazanavir-ritonavir and Efavirenz on Atovaquone Pharmacokinetics in HIV-infected Volunteers|
Further study details as provided by National Institutes of Health Clinical Center (CC):
Primary Outcome Measures
- The primary objective of this study is to determine the steady state pharmacokinetics of 2 doses of atovaquone oral suspension in the presence of ATV/r, EFV, or no ARVs in HIV-infected patients.
- To compare our PK results with the recently reported interaction between a single dose of atovaquone+proguanil and ATV/r and EFV, and the comparator group which consists of HIV-infected subjects, as opposed to a comparator group of healthy subje...
|Study Start Date:||October 31, 2011|
|Study Completion Date:||February 20, 2014|
|Primary Completion Date:||February 20, 2014 (Final data collection date for primary outcome measure)|
The incidence of opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP) and
Toxoplasma gondii have substantially declined in patients with HIV infection due to potent
combination antiretroviral (ARV) therapy and effective prophylaxis. The drug of choice for
prophylaxis and treatment of PCP and toxoplasmosis is trimethoprim-sulfamethoxazole (TMP-SMX)
and sulfadiazine, respectively. In patients who cannot tolerate these first line therapies,
atovaquone is a common alternative. While generally considered safe and effective, a recent
drug interaction study involving a single dose of combination tablet of atovaquone/proguanil
(Malarone ) in HIV-infected patients showed that atovaquone plasma concentrations were
significantly lowered (compared to healthy volunteers) by 75%, 74%, and 46% in patients
taking the ARV medications efavirenz (EFV), lopinavir-ritonavir (LPV/r), and
atazanavir-ritonavir (ATV/r), respectively. The mechanism of this drug interaction is unknown
but is presumably due to induction of uridine diphosphate glucuronsosyltransferase (UGT)
enzymes responsible for the metabolism of atovaquone. The magnitude of this interaction is
such that it strongly suggests a clinically relevant drug interaction between atovaquone and
the aforementioned ARVs. The purpose of this study is to determine whether HIV-infected
subjects receiving ATV/r or EFV-containing ARV regimens, experience reductions in atovaquone
exposure under steady state conditions compared to HIV-infected patients not receiving ARV
In this open-label study, 30 HIV-infected subjects will participate in 1 of 3 groups of 10 (Groups A, B, and C). Group A will consist of 10 subjects who are already receiving combination ARV therapy containing ATV/r; Group B will consist of 10 subjects already receiving combination ARV therapy containing EFV; and Group C will consist of 10 subjects who are not currently receiving ARV therapy. All subjects in Groups A, B, and C will be randomly assigned to either receive atovaquone 750 mg twice daily for 14 days (Phase 1) followed by a 2-6 week washout period, followed by atovaquone 1500 mg twice daily for 14 days (Phase 2), or vice versa. Pharmacokinetic (PK) sampling for atovaquone will occur on Day 14 of Phase 1 and
|Ages Eligible for Study:||18 Years to 70 Years|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- INCLUSION CRITERIA:
- HIV-infected patients stabilized (greater than or equal to 90 days) on ARV regimens containing efavirenz 600 mg daily, or atazanavir/ritonavir 300/100 mg daily or HIV-infected patients not receiving ARV therapy.
- CD4 cells greater than or equal to 350 cells/mm3 for HIV-infected patients not receiving ARV therapy.
- CD4 cells >200 cells/mm3 for HIV-infected patients receiving ARV therapy.
- Virologically suppressed patients receiving ARV therapy (<200 copies/mL on at least 2 consecutive occasions, within 6 months prior to enrollment).
- Females of child bearing potential who are able and willing to prevent pregnancy by (a) practicing abstinence or (b) using effective methods of birth control, such as condoms, during the study period and for 1 month after study completion.
- Subject agrees to storage of specimens for future research.
A subject will be considered eligible for this study only if all of the following criteria are met: ~#o1~ Between the ages of 18 and 70 years.
- Concomitant routine therapy with any prescription, over-the- counter, herbal, or holistic medications that are known or suspected to alter atovaquone including rifampin, rifabutin, and metoclopramide for 14 days prior to study participation.
- Subjects receiving primary or secondary prophylaxis for PCP or toxoplasmosis.
- ARV regimens containing both EFV and ATV/r.
- Subjects receiving hormonal contraceptives within 90 days of Study Day 1.
- Inability to obtain venous access for sample collection.
- Laboratory and/or physical evidence of any active opportunistic infection.
- Positive pregnancy test or breastfeeding female.
- The presence of persistent diarrhea or malabsorption that could interfere with the subject s ability to absorb drugs.
- Drug or alcohol use that may impair safety or adherence.
- History of intolerance or allergic reaction (rash; hives; swollen lips; difficulty breathing) to atovaquone.
- Bleeding disorders (hemophilia, G.I., or intracranial bleeding).
- Organ transplant recipient.
- Documented ongoing problems with medication adherence.
- High likelihood of switching ARV regimen within 12 weeks of the start of the study.
A subject will be ineligible for this study if 1 or more of the following criteria are met:
Diabetes mellitus requiring treatment with insulin, active tuberculosis, cardiac disease (uncontrolled hypertension and/or heart failure etc.), renal disease (chronic or acute renal failure or insufficiency resulting in baseline serum creatinine greater than 1.5 times upper limit of normal [ULN]), untreated/uncontrolled thyroid disease, untreated/uncontrolled psychiatric disease, active hepatitis (liver failure resulting in liver function tests greater than 3 times the ULN, ascites, or jaundice in the absence of ATV), or any other condition that may interfere with the interpretation of the study results or not be in the best interest of the subject in the opinion of the Investigator.
Contacts and LocationsChoosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01479361
Locations Show More
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
Sponsors and CollaboratorsNational Institutes of Health Clinical Center (CC)
|Principal Investigator:||Joseph A Kovacs, M.D.||National Institutes of Health Clinical Center (CC)|
|Responsible Party:||National Institutes of Health Clinical Center (CC)|
|ClinicalTrials.gov Identifier:||NCT01479361 History of Changes|
|Other Study ID Numbers:||120017|
|Study First Received:||November 22, 2011|
|Last Updated:||June 30, 2017|
Keywords provided by National Institutes of Health Clinical Center (CC):Atovaquone
Additional relevant MeSH terms:
ClinicalTrials.gov processed this data on October 20, 2017
This information is provided by ClinicalTrials.gov.