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

Not Applicable

Completed

• Conditions: HIV Infections; Tuberculosis
• Interventions: Drug: Atazanavir; Drug: Rifampin; Drug: Ritonavir

• Registration Number: NCT00096850
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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.

Study Timeline

• Study First Submitted: 2004-11-16
• Study First Submitted QC: 2004-11-16
• Study First Posted: 2004-11-17
• Study Completion: 2007-12
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-28
• Last Update Posted: 2021-11-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1	Atazanavir	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.
1	Rifampin	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.
1	Ritonavir	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.

Primary Outcome Measures

Name	Time	Method
Safety and tolerability of RTV-boosted ATV when coadministered with RIF	Throughout study
Pharmacokinetic parameters of ritonavir (RTV)-boosted ATV when administered concurrently with RIF	Throughout study

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics of RIF	Throughout study
Serum bilirubin concentration	Throughout study
urine thromboxane and prostacyclin concentrations	At study entry and first PK visit
Copy number of cellular drug transporter RNA in peripheral blood mononuclear cells (PBMCs)	Throughout study
UDP-glucuronosyltransferase (UGT)-1A1 genotype	At study entry

Trial Locations

Locations (3)

Vanderbilt Therapeutics CRS; 🇺🇸 Nashville, Tennessee, United States

The Ohio State Univ. AIDS CRS; 🇺🇸 Columbus, Ohio, United States

Stanford CRS; 🇺🇸 Palo Alto, California, United States