Doravirine, Rifapentine and Isoniazid Interaction (DORIIS)

A Phase 1, Open-Label, Fixed-Sequence, Drug Interaction Study to Investigate the Effect of Once-Weekly Rifapentine and Isoniazid on the Pharmacokinetics of Steady-State Doravirine

Drug therapy for persons living with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) co-infected with latent tuberculosis infection (LTBI) is complex. Anti-tuberculosis drugs used to treat LTBI often induce drug metabolizing enzymes that share the same metabolic pathway as antiretroviral drugs used for those living with HIV/AIDS. This study evaluates the drug-drug interaction (DDI) potential of an antiretroviral drug when co-administered with a common anti-tuberculosis regimen of drugs.

Study Overview

• Status: Completed
• Conditions: Latent Tuberculosis; Human Immunodeficiency Virus; Drug Interaction Potentiation; Rifamycins Causing Adverse Effects in Therapeutic Use
• Intervention / Treatment: Drug: Doravirine (DOR); Drug: Rifapentine (RPT); Drug: Isoniazid (INH)

Detailed Description

Rifapentine (RPT) and isoniazid (INH) given once weekly for 12 weeks is commonly used for treating LTBI in adults. For people living with HIV-1, the risks of LTBI is increased. Individuals living with HIV-1 are often on chronic antiretroviral drugs that prevent immunodeficiency and complications associated with infection. Unfortunately, antiretroviral drugs are subject to many DDIs especially with RPT which induces drug clearing enzymes.

Doravirine (DOR) is a newly approved non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. Because RPT induces the metabolic pathway in which DOR is removed, there is concern that taking both concomitantly will result in an unwanted DDI leading to reduced DOR concentrations in the blood. Reduced levels will result in loss of efficacy for the drug and therefore not provide adequate viral suppression in those living with HIV. This study investigates the DDI potential of the once weekly regimen RPT and INH together with DOR in healthy volunteers.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy male or female between 18-60 years old at the time of screening.
2. Have a Body Mass Index (BMI) > 19 and < 33.
3. Weigh > 45 kg but < 120 kg.
4. Non-smoker (tobacco or electronic cigarettes).
5. Negative QuantiFERON-TB Gold at screening.
6. Subjects who agree to abstain from alcohol consumption throughout the duration of the study.
7. Female subjects of childbearing potential must demonstrate a urine beta-hCG consistent with non-pregnancy at the time of the screening visit and agree to the use (and/or have their partner use) of an acceptable method of birth-control at initial screening, during the time of the trial and until two weeks after the last dose of drug following the last treatment period.
8. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.

Exclusion Criteria:

1. History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, dermatologic, psychiatric abnormalities or neurological (including stroke and chronic seizure) diseases.
2. >500 mL blood or plasma donation in the 6 weeks prior to study start
3. Known anaphylactic or severe systemic reactions to any components of doravirine, rifapentine, isoniazid or pyridoxine.
4. Positive HIV, Hepatitis B or Hepatitis C virus. Evidence of prior Hepatitis B infection and immunity is not exclusionary.
5. Latent or active tuberculosis infection. Documented prior fully treated latent tuberculosis is not exclusionary.
6. Females who are postpartum < 12 months.
7. Current drug or alcohol abuse.
8. Received study drug in another study within 4 weeks or within 5 half-lives, which ever occurring first, before first anticipated dose of study drug in this study.
9. Unable to refrain from use of over-the-counter, prescription (unless determined appropriate by the investigator), herbal or natural products, vitamins or supplements, or grapefruit juice/grapefruit products.
10. Any clinical significant findings on lab, ECG or physical exam at screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Experimental; Period 1: DOR twice-daily alone (Study days 1-4) and Period 2: DOR twice-daily with RPT and INH once-weekly (Study days 7-21)

Drug: Doravirine (DOR); Non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection in adults in combination with other antiretroviral agents.; Other Names: Pifeltro; Drug: Rifapentine (RPT); Rifamycin anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection.; Other Names: Priftin; Drug: Isoniazid (INH); Anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection.; Other Names: Generic (various)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Doravirine Maximum Concentration (Cmax)	Doravirine maximum observed concentration during the dosing interval	Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12)	Doravirine area under the plasma-concentration time curve derived from plasma sampling during one dosing interval	Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
Doravirine Oral Clearance (CL/F)	Doravirine apparent oral clearance derived from plasma sampling	Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Event	Safety and tolerability	Days 1-24 post-dose (period 1 and 2) and 31-34 post-dose (post-study)

Collaborators and Investigators

• Sponsor: Walter K. Kraft
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Walter K Kraft, MD, Sidney Kimmel Medical College at Thomas Jefferson University

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 22, 2019
• Primary Completion (ACTUAL): May 20, 2019
• Study Completion (ACTUAL): May 20, 2019

Study Registration Dates

• First Submitted: March 12, 2019
• First Submitted That Met QC Criteria: March 21, 2019
• First Posted (ACTUAL): March 22, 2019

Study Record Updates

• Last Update Posted (ACTUAL): March 27, 2020
• Last Update Submitted That Met QC Criteria: March 16, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Drug-drug interaction; Non-nucleoside reverse transcriptase inhibitor; NNRTI; LTBI; Antimycobacterial
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Slow Virus Diseases; HIV Infections; Tuberculosis; Latent Tuberculosis; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Antitubercular Agents; Antibiotics, Antitubercular; Fatty Acid Synthesis Inhibitors; Rifapentine; Isoniazid
• Other Study ID Numbers: 12690

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No