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

NCT03510468 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 18008718-CC-0087
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Volunteers

Keywords

Antiretroviral Therapy; Human Immunodeficiency Virus; Latent Tuberculosis; Drug-Drug Interactions; Rifamycin

Outcome Measures

Primary Outcomes (10)

• 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 ®

  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 ®

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  Days 14, 22, and 31

Secondary Outcomes (2)

• 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

• Terminal Half-life (t½) of Intracellular Tenofovir-diphosphate

  Days 14, 22, and 31

Study Arms (1)

Pharmacokinetic study in healthy volunteers

EXPERIMENTAL

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.

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

Interventions

Tenofovir alafenamide DRUG

Each tablet contains 25 mg of tenofovir alafenamide.

Also known as: Vemlidy

Pharmacokinetic study in healthy volunteers

Rifapentine DRUG

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).

Also known as: Priftin

Pharmacokinetic study in healthy volunteers

Isoniazid (INH) DRUG

Each tablet is formulated as 100 or 300 mg of isoniazid.

Pharmacokinetic study in healthy volunteers

Pyridoxine DIETARY_SUPPLEMENT

Each tablet contains 50 mg of pyridoxine

Also known as: Vitamin B6

Pharmacokinetic study in healthy volunteers

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Individuals must meet all of the following criteria to be eligible for study participation:
• Ages 18-65 years.
• 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.
• 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).
• Negative QuantiFERON-TB Gold test at screening.
• HIV-negative, as determined by standard serologic assays for HIV infection.
• No laboratory evidence of active or chronic hepatitis A, B, or C infection.
• Willing to abstain from alcohol consumption throughout the study period.
• Agrees to genetic testing and storage of specimens for future research.
• Able to provide informed consent.
• Negative serum or urine pregnancy test for females of child-bearing potential.
• 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.
• Male or female condom.
• Diaphragm or cervical cap with a spermicide.
• Intrauterine device without hormones.

You may not qualify if:

• Individuals meeting any of the following criteria will be excluded from study participation:
• Known hypersensitivity to TAF, tenofovir disoproxil fumarate (TDF), INH, RPT, and other rifamycin analogues.
• History or presence of any of the following:
• Latent or active TB infection.
• 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).
• 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).
• Respiratory disease that is uncontrolled or requires daily treatment with medication (eg, asthma or chronic obstructive pulmonary disease).
• Cardiovascular disease (eg, hypertension \[systolic blood pressure \> 140 mm Hg or diastolic blood pressure \> 90 mm Hg\], heart failure, or arrhythmia).
• Metabolic disorders (eg, diabetes mellitus).
• Hematologic or bleeding disorders (eg, anemia, hemophilia, serious/major bleeding events, menorrhagia \[female participants\]).
• Immunologic disorders.
• Hormonal or endocrine disorders.
• Psychiatric illness that would interfere with their ability to comply with study procedures or that requires daily treatment with medication.
• Seizure disorder, with the exception of childhood febrile seizures.
• 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

Sponsors & Collaborators

• National Institutes of Health Clinical Center (CC): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome; Latent Tuberculosis

Interventions

tenofovir alafenamide; rifapentine; Isoniazid; Pyridoxine; Vitamin B 6

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Latent Infection

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Picolines

Results Point of Contact

• Title: Dr. Joseph Kovacs
• Organization: Clinical Center

jkovacs@mail.nih.gov

+1 301 496 9907

Study Officials

• Joseph A Kovacs, M.D.

  National Institutes of Health Clinical Center (CC)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2018
• First Posted: April 27, 2018
• Study Start: June 12, 2018
• Primary Completion: November 15, 2022
• Study Completion: December 21, 2022
• Last Updated: August 13, 2024
• Results First Posted: October 25, 2023

Record last verified: 2022-12-21

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)