Background: Human immunodeficiency virus (HIV) is treated with antiretroviral drugs. Many people with HIV also have the lung infection tuberculosis (TB). Most TB treatments are complicated. A simpler treatment of two TB drugs can be taken once a week. Researchers want to study how the HIV and TB drugs affect each other so people who take both can be treated safely. Objective: To study if rifapentine and isoniazid affect blood levels of the common antiretroviral TAF. Eligibility: Healthy adults ages 18-65 without HIV, TB, or hepatitis Design: Participants will fast before the screening visit. They will have a medical history, physical exam, and blood tests. Women may have a pregnancy test. During the study, participants must: Use effective birth control Not take most medicine Not drink alcohol At the baseline visit, participants will repeat screening tests and get TAF tablets. Participants will take TAF once a day for 31 days. They will keep track of doses and side effects. Over 32 days, participants will have 4 long visits and 4 short. At all visits, participants will: Fast the night before Get food Take that day's TAF Review their TAF supply Have pregnancy and blood tests Report side effects At 3 visits, participants will also take the 2 TB drugs and vitamin B6. At 3 long visits, participants will also have blood collected 8 times over 8 hours by plastic tube in an arm vein. Around Day 46, participants will fast and have blood and pregnancy tests. Two weeks later, they will get a call to see how they are feeling.
Rifapentine (RPT) is a long-acting rifamycin that can be used weekly with isoniazid (INH) as a first-line regimen in the treatment of latent tuberculosis infection (LTBI). Although this regimen offers several potential benefits, the use of weekly RPT plus INH is limited in adults infected with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) due to lack of drug interaction data with antiretrovirals (ARVs). Tenofovir alafenamide (TAF) is a preferred backbone agent by the current Department of Health and Human Services ARV guidelines and is a part of multiple recommended first-line regimens for the treatment of HIV. However, the use of TAF with rifamycins, including RPT, is not recommended due to potential drug interactions. Thus, the purpose of this study is to determine the effects of concomitant RPT and INH administration on the steady state pharmacokinetics (PK) of plasma TAF, plasma tenofovir (TFV), and intracellular TFV diphosphate (dp). This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate the steady state PK of TAF, TFV, and TFV-dp with coadministration of once-weekly RPT + INH administered at doses used to treat LTBI. The study will consist of two phases: (1) TAF once daily alone (days 1-14) and (2) TAF once daily + weight-based RPT + INH once weekly (days 15-31). Participants will undergo periodic serial ARV PK blood draws over 24 hours on days 14-15, 22-23, and 31-32. TAF, TFV, and TFV-dp PK will be determined using non-compartmental methods. The following PK parameters will be compared between phases: area under the curve over the dosing interval, maximum plasma concentration, time to maximum plasma concentration, terminal half-life, apparent oral clearance, and minimum plasma concentration. Adverse events will be graded and recorded.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
51
Each tablet contains 25 mg of tenofovir alafenamide.
Each tablet contains 150 mg of rifapentine. Participants who weigh 45 to \< 50 kg will take 750 mg (5 tablets), and participants who weigh (Bullet) 50 kg will take 900 mg (6 tablets).
Each tablet is formulated as 100 or 300 mg of isoniazid.
Each tablet contains 50 mg of pyridoxine
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Plasma Area Under the Curve (AUC) for Tenofovir Alafenamide (TAF) During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)
Plasma area under the curve (AUC) during the dosing interval of 0 to 24 hours (AUC0-24hr) on day 14, 22, and 31 of TAF was calculated using the linear-up/log-down trapezoidal rule using noncompartmental methods on Phoenix WinNonlin ®
Time frame: 0-24 hours post dosing on days 14, 22, and 31
Plasma Area Under the Curve (AUC) for Tenofovir (TFV) During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)
Plasma area under the curve (AUC) during the dosing interval of 0 to 24 hours (AUC0-24hr) on day 14, 22, and 31 of TFV was calculated using the linear-up/log-down trapezoidal rule using noncompartmental methods on Phoenix WinNonlin ®
Time frame: 0-24 hours post dosing on days 14, 22, and 31
Maximum Total Plasma Concentration (Cmax) for Tenofovir Alafenamide (TAF)
Maximum total plasma concentration (Cmax) following a 25mg dose of TAF on day 14, 22, and 31. Cmax for TAF was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.
Time frame: Days 14, 22, and 31
Maximum Total Plasma Concentration (Cmax) for Tenofovir (TFV)
Maximum total plasma concentration (Cmax) following a 25mg dose of tenofovir alafenamide (TAF) on day 14, 22, and 31. Cmax for TFV was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.
Time frame: Days 14, 22, and 31
Time to Maximum Plasma Concentration (Tmax) for Tenofovir Alafenamide (TAF)
Time to maximum total plasma concentration (Cmax) following a 25mg dose of TAF on day 14, 22, and 31. Tmax for TAF was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.
Time frame: Days 14, 22, and 31
Time to Maximum Plasma Concentration (Tmax) for Tenofovir (TFV)
Time to maximum total plasma concentration (Cmax) following a 25mg dose of TAF on day 14, 22, and 31. Tmax for TFV was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.
Time frame: Days 14, 22, and 31
Terminal Half-life (t½) of Tenofovir (TFV)
Half-life calculated as natural log of 2 \[ln(2)\]/lambda Z of TFV on day 14, 22, and 31.
Time frame: Days 14, 22, and 31
Apparent Oral Clearance (CL/F) of Tenofovir Alafenamide (TAF)
Apparent oral clearance of TAF was calculated as "dose/plasma area under the curve (AUC)" on day 14, 22, and 31.
Time frame: Days 14, 22, and 31
Minimum Total Plasma Concentration (Cmin) for Tenofovir Alafenamide (TAF)
Minimum total plasma concentration (Cmin) following a 25mg dose of TAF on day 14, 22, and 31. Cmin for TAF was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.
Time frame: Days 14, 22, and 31
Minimum Total Plasma Concentration (Cmin) for Tenofovir (TFV)
Minimum total plasma concentration (Cmin) following a 25mg dose of tenofovir alafenamide (TAF) on day 14, 22, and 31. Cmin for TFV was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.
Time frame: Days 14, 22, and 31
Plasma Area Under the Curve (AUC) for Intracellular Tenofovir Di-phosphate During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)
Plasma area under the curve (AUC) during the dosing interval of 0 to 24 hours (AUC0-24hr) on day 14, 22, and 31 of intracellular tenofovir di-phosphate using the linear-up/log-down trapezoidal rule using noncompartmental methods on Phoenix WinNonlin ®
Time frame: 0-24 hours post dosing on days 14, 22, and 31
Terminal Half-life (t½) of Intracellular Tenofovir-diphosphate
Half-life calculated as natural log of 2\[ ln(2)\]/lambda Z of TFV on day 14, 22, and 31.
Time frame: Days 14, 22, and 31
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.