Clinical trial NCT00096850: Safety, Tolerability, and Blood Levels of Ritonavir-Boosted Atazanavir and Rifampin When Taken Together in HIV Uninfected Adults
Official title: Safety, Tolerability, and Pharmacokinetic Interactions of Atazanavir and Rifampin in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Tuberculosis
Keywords: HIV Seronegativity
Antitubercular agents
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
First posted: 2004-11-17
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Rifampin (RIF) is used for the treatment of tuberculosis (TB), an infectious disease that affects many people with HIV. RIF was shown to lower concentrations and decrease the effectiveness of some anti-HIV drugs, including the HIV protease inhibitor (PI) atazanavir (ATV) boosted with ritonavir (RTV). The purpose of this study is to determine the interactions between RTV-boosted ATV and evaluate the safety and tolerability of giving these drugs together in HIV uninfected adults.

Detailed description: TB is common in resource-limited countries, and people infected with HIV are especially at risk for TB infection. The antituberculous drug RIF lowers plasma concentrations of PIs by increasing the activity of enzymes responsible for PI breakdown. RIF has been shown to reduce PI effectiveness, a particular concern for HIV infected patients who are also being treated for TB. RTV has been shown to delay the plasma clearance of ATV and increase the plasma half-life of ATV. This study will evaluate the safety, tolerability, and pharmacokinetic (PK) interactions of RTV-boosted ATV, taken concurrently with RIF in HIV uninfected people.

Medical and medication history, a complete physical exam, blood collection, and an electrocardiogram (ECG) will occur at screening. Participants will be enrolled in this study for 41 to 58 days; there will be 3 dosing periods. From Days 1 to 8, participants will receive 600 mg RIF every 24 hours. From Days 9 to 19, participants will receive 300 mg ATV and 100 mg RTV every 12 hours and 600 mg RIF every 24 hours. From Days 20 to 27, participants will receive 400 mg ATV and 100 mg RTV every 12 hours and 600 mg RIF every 24 hours. Study visits will occur at entry; at Days 5, 8, 11, 14, 19, 23, and 27; and at an additional visit between Days 41 and 48. Blood and urine collection will occur at all visits. A targeted physical exam, an ECG, and blood collection for PK analysis will occur at Days 8, 19, and 27.

Eligibility criteria: Note: As of 11/27/06, enrollment into Version 1.0 of the study is now closed. Any new study participants will enroll under Version 2.0.

Inclusion Criteria:

* HIV uninfected
* Normal creatinine clearance
* Willing to use acceptable means of contraception during the study and for at least 6 weeks after stopping study medications

Exclusion Criteria:

* Using or anticipating use of certain medications, including any medication metabolized by CYP3A
* Active drug use or dependence that, in the opinion of the investigator, may interfere with the study
* Cannot stop consuming alcoholic beverages, grapefruit, or grapefruit juice for the duration of the study
* Cannot stop consuming coffee or caffeine-containing products for 12 hours prior to Day 8, 19, and 27 PK studies
* Serious illness that, in the opinion of the investigator, may interfere with the study
* Hospitalization for any reason within 14 days prior to study entry
* History of hypersensitivity to study drugs or their formulations
* Active or previous history of cardiovascular, kidney, liver, blood, neurologic, gastrointestinal, psychiatric, endocrine, or immunologic disease. Patients with chronic illnesses such as hypertension, coronary heart disease, arthritis, diabetes, or chronic gastrointestinal conditions that may affect drug absorption are also excluded.
* ECG showing first-degree or greater heart block or a QT interval greater than 440 msec within 30 days of study entry
* Previous participation in this study
* Pregnancy or breastfeeding

Primary outcomes:
measure: Pharmacokinetic parameters of ritonavir (RTV)-boosted ATV when administered concurrently with RIF
timeFrame: Throughout study
measure: Safety and tolerability of RTV-boosted ATV when coadministered with RIF
timeFrame: Throughout study
Secondary outcomes:
measure: Pharmacokinetics of RIF
timeFrame: Throughout study
measure: Copy number of cellular drug transporter RNA in peripheral blood mononuclear cells (PBMCs)
timeFrame: Throughout study
measure: UDP-glucuronosyltransferase (UGT)-1A1 genotype
timeFrame: At study entry
measure: Serum bilirubin concentration
timeFrame: Throughout study
measure: urine thromboxane and prostacyclin concentrations
timeFrame: At study entry and first PK visit
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford CRS
state: California
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS
state: Tennessee
Study officials:
affiliation: Infectious Diseases, Vanderbilt University Medical Center
name: David W. Haas, MD
role: STUDY_CHAIR
References:
citation: Finch CK, Chrisman CR, Baciewicz AM, Self TH. Rifampin and rifabutin drug interactions: an update. Arch Intern Med. 2002 May 13;162(9):985-92. doi: 10.1001/archinte.162.9.985.
citation: Fujiwara PI, Clevenbergh P, Dlodlo RA. Management of adults living with HIV/AIDS in low-income, high-burden settings, with special reference to persons with tuberculosis. Int J Tuberc Lung Dis. 2005 Sep;9(9):946-58.
citation: Kashuba AD. Drug-drug interactions and the pharmacotherapy of HIV infection. Top HIV Med. 2005 Jun-Jul;13(2):64-9.
citation: Musial BL, Chojnacki JK, Coleman CI. Atazanavir: a new protease inhibitor to treat HIV infection. Am J Health Syst Pharm. 2004 Jul 1;61(13):1365-74. doi: 10.1093/ajhp/61.13.1365.
citation: Orrick JJ, Steinhart CR. Atazanavir. Ann Pharmacother. 2004 Oct;38(10):1664-74. doi: 10.1345/aph.1D394. Epub 2004 Sep 7.
citation: Acosta EP, Kendall MA, Gerber JG, Alston-Smith B, Koletar SL, Zolopa AR, Agarwala S, Child M, Bertz R, Hosey L, Haas DW. Effect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice daily. Antimicrob Agents Chemother. 2007 Sep;51(9):3104-10. doi: 10.1128/AAC.00341-07. Epub 2007 Jun 18.