Safety, Tolerability, and Blood Levels of Ritonavir-Boosted Atazanavir and Rifampin When Taken Together in HIV Uninfected Adults

HIV Infections Clinical Trial

Official title:

Safety, Tolerability, and Pharmacokinetic Interactions of Atazanavir and Rifampin in Healthy Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00096850
• Other study ID #: A5213
• Secondary ID: 10021ACTG A5213
• Status: Completed
• Phase: N/A
• Est. completion date: December 2007

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: December 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• HIV Infections
• Tuberculosis

Intervention

Drug:
• Atazanavir
From Days 9 to 19, participants will receive a 300 mg tablet orally daily. From Days 20 to 27, participants will receive a 400 mg tablet orally daily.
• Rifampin
From Days 1 to 27, participants will receive a 600 mg tablet orally daily.
• Ritonavir
From Days 9 to 19, participants will receive a 100 mg tablet orally daily. From Days 20 to 27, participants will receive a 100 mg tablet orally twice daily.

Locations

Country	Name	City	State
United States	The Ohio State Univ. AIDS CRS	Columbus	Ohio
United States	Vanderbilt Therapeutics CRS	Nashville	Tennessee
United States	Stanford CRS	Palo Alto	California

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	AIDS Clinical Trials Group

Country where clinical trial is conducted

United States, 

References & Publications (6)

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 Ag — View 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. Review. — View 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. Review. — View Citation

Kashuba AD. Drug-drug interactions and the pharmacotherapy of HIV infection. Top HIV Med. 2005 Jun-Jul;13(2):64-9. Review. — View 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. Review. Erratum in: Am J Health Syst Pharm. 2004 Nov 1;61(21):2243. — View Citation

Orrick JJ, Steinhart CR. Atazanavir. Ann Pharmacother. 2004 Oct;38(10):1664-74. Epub 2004 Sep 7. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetic parameters of ritonavir (RTV)-boosted ATV when administered concurrently with RIF		Throughout study
Primary	Safety and tolerability of RTV-boosted ATV when coadministered with RIF		Throughout study
Secondary	Pharmacokinetics of RIF		Throughout study
Secondary	Copy number of cellular drug transporter RNA in peripheral blood mononuclear cells (PBMCs)		Throughout study
Secondary	UDP-glucuronosyltransferase (UGT)-1A1 genotype		At study entry
Secondary	Serum bilirubin concentration		Throughout study
Secondary	urine thromboxane and prostacyclin concentrations		At study entry and first PK visit

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