Clinical trial NCT03510468: Impact of Weekly Administration of Rifapentine and Isoniazid on Steady State Pharmacokinetics of Tenofovir Alafenamide in Healthy Volunteers (YODA)
Official title: Impact of Weekly Administration of Rifapentine and Isoniazid on Steady State Pharmacokinetics of Tenofovir Alafenamide in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Antiretroviral Therapy
Human Immunodeficiency Virus
Latent Tuberculosis
Drug-Drug Interactions
Rifamycin
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2018-04-27
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: * PARTICIPANT INCLUSION CRITERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

1. Ages 18-65 years.
2. Weight greater than or equal to 45 kg and less than or equal to 120 kg OR body mass index greater than or equal to 18.0 and \< 30.
3. Judged to be healthy based on medical history, physical examination, vital signs, and clinical laboratory tests: liver function tests (AST, alanine transaminase( ALT), Tbili) less than or equal to upper limit of normal \[ULN\], serum creatinine (SCr) less than or equal to ULN, platelets (PLT) \> 150,000/microL, hemoglobin (Hgb) \> 13 g/dL (males); greater than or equal to 12g/dL (females), C-reactive protein (CRP) less than or equal to ULN, creatine kinase (CK) less than or equal to 2x ULN, fasting total cholesterol \< 240 mg/dL, or fasting triglycerides \< 240 mg/dL, urine glucose \< grade 2 (per Division of Acquired Immunodeficiency Syndrome (DAIDS) adverse event (AE) table), urine protein \< grade 2 (per DAIDS AE table).
4. Negative QuantiFERON-TB Gold test at screening.
5. HIV-negative, as determined by standard serologic assays for HIV infection.
6. No laboratory evidence of active or chronic hepatitis A, B, or C infection.
7. Willing to abstain from alcohol consumption throughout the study period.
8. Agrees to genetic testing and storage of specimens for future research.
9. Able to provide informed consent.
10. Negative serum or urine pregnancy test for females of child-bearing potential.
11. Participants must agree not to become pregnant or impregnate a partner for the duration of the study. The use of hormonal contraceptives will not be permitted. Study participants must use one of the following methods of birth control when engaging in sexual activities that can result in pregnancy, beginning at screening until the final study visit.

    1. Male or female condom.
    2. Diaphragm or cervical cap with a spermicide.
    3. Intrauterine device without hormones.

PARTICIPANT EXCLUSION CRITERIA:

Individuals meeting any of the following criteria will be excluded from study participation:

1. Known hypersensitivity to TAF, tenofovir disoproxil fumarate (TDF), INH, RPT, and other rifamycin analogues.
2. History or presence of any of the following:

   1. Latent or active TB infection.
   2. Gastrointestinal (GI) disease that is uncontrolled, requires daily treatment with medication, or would interfere with a participant s ability to absorb drugs (eg, diarrhea, pancreatitis, or peptic ulcer disease).
   3. Renal impairment (chronic renal insufficiency of any chronic kidney disease stage, or acute renal failure not induced by drug therapy defined as estimated glomerular filtration rate (eGFR) \< 90 mL/min or SCr \> ULN).
   4. Respiratory disease that is uncontrolled or requires daily treatment with medication (eg, asthma or chronic obstructive pulmonary disease).
   5. Cardiovascular disease (eg, hypertension \[systolic blood pressure \> 140 mm Hg or diastolic blood pressure \> 90 mm Hg\], heart failure, or arrhythmia).
   6. Metabolic disorders (eg, diabetes mellitus).
   7. Hematologic or bleeding disorders (eg, anemia, hemophilia, serious/major bleeding events, menorrhagia \[female participants\]).
   8. Immunologic disorders.
   9. Hormonal or endocrine disorders.
   10. Psychiatric illness that would interfere with their ability to comply with study procedures or that requires daily treatment with medication.
   11. Seizure disorder, with the exception of childhood febrile seizures.
   12. Any current or history of malignancy, with the exception of cutaneous basal cell carcinoma,non-invasive squamous cell carcinoma, or any other malignancies not requiring systemic

       therapy.
   13. Current or history of osteopenia and osteoporosis.
3. Current participation in an ongoing investigational drug protocol or use of any investigational drug within 30 days (based on last dose received) prior to receipt of any study drugs.
4. Therapy with any prescription, over-the-counter (OTC), herbal, or holistic medications, including hormonal contraceptives by any route, within 5 half-lives of the agent prior to receipt of any study medications will not be permitted with the following exception: Intermittent or short-course therapy (\<14 days) with prescription or OTC medications, herbals, or holistic medications within the screening period prior to starting study drugs may be permitted, and will be reviewed by investigators on a case-by-case basis for potential drug interactions. Receipt of influenza vaccination will be allowed prior to, during, and/or after the study.
5. Inability to obtain venous access for sample collection.
6. Inability to swallow whole capsules and/or tablets.
7. Pregnant or breastfeeding.
8. Drug use that may impair safety or adherence.
9. Use of nicotine-containing products, including cigarettes and chewing tobacco, nicotine patches, gum, electronic cigarettes, etc.
10. Organ or stem cell transplant recipient.
11. Uncorrected and persistent electrolyte abnormalities (eg, potassium, magnesium, and calcium).
12. Current alcohol use disorders (DSM-5 criteria).
13. Fasting total cholesterol \> 240 mg/dL or fasting triglycerides \> 240 mg/dL at screening.
14. Any condition that, in the opinion of the investigator, contraindicates participation in this study.

Primary outcomes:
measure: Plasma Area Under the Curve (AUC) for Tenofovir Alafenamide (TAF) During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)
timeFrame: 0-24 hours post dosing on days 14, 22, and 31
measure: Plasma Area Under the Curve (AUC) for Tenofovir (TFV) During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)
timeFrame: 0-24 hours post dosing on days 14, 22, and 31
measure: Maximum Total Plasma Concentration (Cmax) for Tenofovir Alafenamide (TAF)
timeFrame: Days 14, 22, and 31
measure: Maximum Total Plasma Concentration (Cmax) for Tenofovir (TFV)
timeFrame: Days 14, 22, and 31
measure: Time to Maximum Plasma Concentration (Tmax) for Tenofovir Alafenamide (TAF)
timeFrame: Days 14, 22, and 31
measure: Time to Maximum Plasma Concentration (Tmax) for Tenofovir (TFV)
timeFrame: Days 14, 22, and 31
measure: Terminal Half-life (t½) of Tenofovir (TFV)
timeFrame: Days 14, 22, and 31
measure: Apparent Oral Clearance (CL/F) of Tenofovir Alafenamide (TAF)
timeFrame: Days 14, 22, and 31
measure: Minimum Total Plasma Concentration (Cmin) for Tenofovir Alafenamide (TAF)
timeFrame: Days 14, 22, and 31
measure: Minimum Total Plasma Concentration (Cmin) for Tenofovir (TFV)
timeFrame: Days 14, 22, and 31
Secondary outcomes:
measure: Plasma Area Under the Curve (AUC) for Intracellular Tenofovir Di-phosphate During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)
timeFrame: 0-24 hours post dosing on days 14, 22, and 31
measure: Terminal Half-life (t½) of Intracellular Tenofovir-diphosphate
timeFrame: Days 14, 22, and 31
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institutes of Health Clinical Center (CC)
name: Joseph A Kovacs, M.D.
role: PRINCIPAL_INVESTIGATOR
References: