Impact of Weekly Administration of Rifapentine and Isoniazid on Steady State Pharmacokinetics of Tenofovir Alafenamide in Healthy Volunteers (YODA)

Phase 1

Completed

Conditions: Healthy Volunteers

Interventions: Drug: Tenofovir alafenamide
Drug: Rifapentine
Drug: Isoniazid (INH)
Dietary Supplement: Pyridoxine

Registration Number: NCT03510468

Lead Sponsor: National Institutes of Health Clinical Center (CC)

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 51

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Pharmacokinetic study in healthy volunteers	Isoniazid (INH)	Healthy volunteers received Tenofovir alafenamide (TAF) 25 mg once daily for 14 days followed by TAF 25 mg once daily and Rifapentine (RPT) dosed by weight in 150-mg tablet increments (maximum oral dose of 900 mg) 750 or 900 mg (depending on weight) and Isoniazid (INH+ pyridoxine), 15 mg/kg (up to 900 mg) once weekly from days 15-31.
Pharmacokinetic study in healthy volunteers	Pyridoxine	Healthy volunteers received Tenofovir alafenamide (TAF) 25 mg once daily for 14 days followed by TAF 25 mg once daily and Rifapentine (RPT) dosed by weight in 150-mg tablet increments (maximum oral dose of 900 mg) 750 or 900 mg (depending on weight) and Isoniazid (INH+ pyridoxine), 15 mg/kg (up to 900 mg) once weekly from days 15-31.
Pharmacokinetic study in healthy volunteers	Tenofovir alafenamide	Healthy volunteers received Tenofovir alafenamide (TAF) 25 mg once daily for 14 days followed by TAF 25 mg once daily and Rifapentine (RPT) dosed by weight in 150-mg tablet increments (maximum oral dose of 900 mg) 750 or 900 mg (depending on weight) and Isoniazid (INH+ pyridoxine), 15 mg/kg (up to 900 mg) once weekly from days 15-31.
Pharmacokinetic study in healthy volunteers	Rifapentine	Healthy volunteers received Tenofovir alafenamide (TAF) 25 mg once daily for 14 days followed by TAF 25 mg once daily and Rifapentine (RPT) dosed by weight in 150-mg tablet increments (maximum oral dose of 900 mg) 750 or 900 mg (depending on weight) and Isoniazid (INH+ pyridoxine), 15 mg/kg (up to 900 mg) once weekly from days 15-31.

Primary Outcome Measures

Name	Time	Method
Terminal Half-life (t½) of Tenofovir (TFV)	Days 14, 22, and 31	Half-life calculated as natural log of 2 \[ln(2)\]/lambda Z of TFV on day 14, 22, and 31.
Plasma Area Under the Curve (AUC) for Tenofovir Alafenamide (TAF) During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)	0-24 hours post dosing on days 14, 22, and 31	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 ®
Plasma Area Under the Curve (AUC) for Tenofovir (TFV) During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)	0-24 hours post dosing on days 14, 22, and 31	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 to Maximum Plasma Concentration (Tmax) for Tenofovir Alafenamide (TAF)	Days 14, 22, and 31	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.
Maximum Total Plasma Concentration (Cmax) for Tenofovir Alafenamide (TAF)	Days 14, 22, and 31	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.
Maximum Total Plasma Concentration (Cmax) for Tenofovir (TFV)	Days 14, 22, and 31	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.
Minimum Total Plasma Concentration (Cmin) for Tenofovir Alafenamide (TAF)	Days 14, 22, and 31	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.
Minimum Total Plasma Concentration (Cmin) for Tenofovir (TFV)	Days 14, 22, and 31	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 to Maximum Plasma Concentration (Tmax) for Tenofovir (TFV)	Days 14, 22, and 31	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.
Apparent Oral Clearance (CL/F) of Tenofovir Alafenamide (TAF)	Days 14, 22, and 31	Apparent oral clearance of TAF was calculated as "dose/plasma area under the curve (AUC)" on day 14, 22, and 31.

Secondary Outcome Measures

Name	Time	Method
Plasma Area Under the Curve (AUC) for Intracellular Tenofovir Di-phosphate During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)	0-24 hours post dosing on days 14, 22, and 31	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 ®
Terminal Half-life (t½) of Intracellular Tenofovir-diphosphate	Days 14, 22, and 31	Half-life calculated as natural log of 2\[ ln(2)\]/lambda Z of TFV on day 14, 22, and 31.