Impact of Weekly Administration of Rifapentine and Isoniazid on Steady State Pharmacokinetics of Tenofovir Alafenamide in Healthy Volunteers (YODA)
Condition: Healthy Volunteers
Intervention: Tenofovir alafenamide; Rifapentine; Isoniazid (INH); Pyridoxine
Intervention description: 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
Intervention MeSH terms: Pyridoxine; Vitamin B 6; Tenofovir; Isoniazid; Rifapentine
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 51.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Antiretroviral Therapy; Human Immunodeficiency Virus; Latent Tuberculosis; Drug-Drug Interactions; Rifamycin

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....
    

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.