Impact of Once-Weekly Rifapentine and Isoniazid on the Steady State Pharmacokinetics of Dolutegravir and Darunavir Boosted With Cobicistat in Healthy Volunteers

NCT02771249 | Completed Phase 1 FDA Drug

• 2 other identifiers: 16011216-CC-0112
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

People with human immunodeficiency virus (HIV) often take several medicines to control HIV. Dolutegravir and darunavir boosted with cobicistat are HIV medicines that people may take. They may also need to take medicines for an infection called latent tuberculosis (TB). Researchers think a once-weekly treatment for latent TB would be easier for people with HIV to take. This once weekly treatment consists of two drugs: rifapentine and isoniazid. However, they need to see how TB drugs and HIV drugs interact. Objective: To learn how anti-HIV and anti-TB drugs affect each other so that people taking these drugs together can be treated safely. Eligibility: Healthy adults ages 18 65. Design: Participants will be screened with a medical history and physical exam. They will have vital signs taken and give a blood sample. Women will have a pregnancy test. Participants cannot take any other medicines during the study, including vitamins. Only occasional, infrequent use of acetaminophen (Tylenol , max 2000 mg/day), ibuprofen (Motrin or Advil ), naproxen (Aleve ), loperamide (Imodium ), and/or antihistamines (such as Benadryl , Zyrtec , Claritin , etc.) will be allowed. Participants will be assigned to one of three groups. Each group will take a different study drug, once or twice a day, for 19 23 days. At the baseline study visit, they will get a supply of the study drug tablets and instructions for taking them. Participants will keep a medicine diary to serve as a memory aid for taking medicine and reporting any side effects that they may experience. Participants will have 8 or 9 study visits over about 40 days. The number of visits depends on which group the person is assigned to. All visits will take place at the NIH Clinical Center. Participants will fast before study visits. The baseline visit will last about 2 3 hours. There will be 3-4 long visits that will last for about 12 hours. The other 4-5 visits will last about 1 hour. During all study visits, screening procedures will be repeated. During long visits, an intravenous (IV) line will be inserted into an arm vein with a needle. It will be used to take blood.

Conditions

HIV Infected Population With Latent Tuberculosis

Keywords

Fixed Sequence; Intrasubject Drug-Drug Interaction; Open-Label

Outcome Measures

Primary Outcomes (1)

• Area-under-the-curve during the dosing interval of 0 to t (AUC0-t), maximum total plasma concentration (Cmax), time to maximum plasma concentration (t-max), terminal halflife (t1/2), apparent oral clearance (CL/F)

  To assess the effects of once weekly administration of RPT and INH given at doses used for treating LTBI on the steady state PK of DRV/c

  Days 4 14, and 19

Secondary Outcomes (1)

• AEs and abnormal laboratory values graded according to the Division of AIDS AE Table, laboratory measures: hepatic & renal function, lipids, complete blood count, creatine kinase & lipase

  Day 34

Study Arms (1)

Arm B

EXPERIMENTAL

Arm B will be comprised of two phases: (1) DRV/c once daily alone (days 1-4) and (2) DRV/c once daily + RPT and INH once weekly (days 5-19).

Drug: rifapentene (RPT); Drug: darunavir/cobicistat (DRV/c); Drug: Isoniazid (INH); Dietary Supplement: Pyridoxine

Interventions

rifapentene (RPT) DRUG

RPT is a long-acting rifamycin used in combination with INH in the treatment of LTBI.

Arm B

darunavir/cobicistat (DRV/c) DRUG

DRV is a protease inhibitor (PI) indicated in the treatment of HIV infection.33 DRV requires coadministration with RTV (100 mg once or twice daily) or COBI (150 mg daily), the latter of which has been coformulated into a fixed-dose tablet with DRV (DRV/c 800/150 mg).

Arm B

Isoniazid (INH) DRUG

INH is an antimycobacterial agent that can be used alone or in combination with RPT for the treatment of LTBI. Given with Pyridoxine (vitamin B6)

Arm B

Pyridoxine DIETARY_SUPPLEMENT

Arm B

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A subject will be considered eligible for this study only if all of the following criteria are met:
• Ages 18 - 65 years
• Weight greater than or equal to 45 kg and less than or equal to 120; BMI 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, ALT, Tbili) greater than or equal to upper limit of normal \[ULN\], serum creatinine (SCr) less than or equal to ULN, CK less than or equal to 2X ULN, platelets (PLT) \>150,0000/mm3, hemoglobin (Hgb) \>11 g/dL), C-reactive protein (CRP) less than or equal to ULN)
• Negative QuantiFERON-TB Gold test at screening
• HIV-negative, as determined by standard serologic assays for HIV infection.
• No laboratory evidence of active Hepatitis A, B, or C infection
• Willing to abstain from alcohol consumption throughout the study period
• Subject agrees to genetic testing and storage of specimens for future research
• Negative serum or urine pregnancy test for females of child-bearing potential
• For female subjects able to become pregnant (i.e., have not undergone surgical sterilization or are not postmenopausal), willingness to prevent pregnancy during the study period by:
• Practicing absolute abstinence from sexual contact or
• Committing to use of effective non-hormonal and/or barrier methods of birth control during any and all sexual encounters. Acceptable methods are as follows:
• Condom, diaphragm, or cervical cap with a spermicide
• Intrauterine device (IUD) without hormones

You may not qualify if:

• A subject will be ineligible for this study if 1, or more, of the following criteria are met:
• Known hypersensitivity to dolutegravir, darunavir, cobicistat, rifapentine and other rifamycin analogues, or isoniazid
• History of type 1 hypersensitivity reaction to sulfonamides
• History or presence of any of the following:
• Latent or active TB infection
• Gastrointestinal disease that is uncontrolled, requires daily treatment with medication, or would interfere with a subject s ability to absorb drugs (diarrhea, pancreatitis, peptic ulcer disease, etc.),
• Renal impairment (chronic renal insufficiency of any CKD stage, or acute renal failure not induced by drug therapy defined as GFR \< 90 ml/min)
• Respiratory disease that is uncontrolled or requires daily treatment with medication (asthma, chronic obstructive pulmonary disease, etc.)
• Cardiovascular disease (hypertension \[systolic blood pressure \>140 mmHg or diastolic blood pressure \> 90 mmHg\], heart failure, arrhythmia, etc.)
• Metabolic disorders (diabetes mellitus, etc.)
• Hematologic or bleeding disorders (anemia, hemophilia, serious/major bleeding events, menorrhagia (female subjects), etc.)
• Immunologic disorders
• Hormonal or endocrine disorders
• Psychiatric illness that would interfere with his or her ability to comply with study procedures or that requires daily treatment with medication
• Seizure disorder, with the exception of childhood febrile seizures

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 Publications (2)

• Martinson NA, Barnes GL, Moulton LH, Msandiwa R, Hausler H, Ram M, McIntyre JA, Gray GE, Chaisson RE. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med. 2011 Jul 7;365(1):11-20. doi: 10.1056/NEJMoa1005136.

  PMID: 21732833 BACKGROUND

• Brooks KM, George JM, Pau AK, Rupert A, Mehaffy C, De P, Dobos KM, Kellogg A, McLaughlin M, McManus M, Alfaro RM, Hadigan C, Kovacs JA, Kumar P. Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine. Clin Infect Dis. 2018 Jul 2;67(2):193-201. doi: 10.1093/cid/ciy082.

  PMID: 29415190 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

cobicistat mixture with darunavir; Isoniazid; Pyridoxine

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Vitamin B 6; Picolines

Study Officials

• Joseph A Kovacs, M.D.

  National Institutes of Health Clinical Center (CC)

  PRINCIPAL INVESTIGATOR

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: May 12, 2016
• First Posted: May 13, 2016
• Study Start: June 3, 2016
• Primary Completion: August 17, 2021
• Study Completion: August 17, 2021
• Last Updated: April 18, 2022

Record last verified: 2021-12-28

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)