Doravirine, Rifapentine and Isoniazid Interaction

Human Immunodeficiency Virus Clinical Trial

— DORIIS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03886701
• Other study ID #: 12690
• Status: Completed
• Phase: Phase 1
• Start date: April 22, 2019
• Est. completion date: May 20, 2019

Study information

• Verified date: March 2020
• Source: Thomas Jefferson University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: May 20, 2019
• Est. primary completion date: May 20, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Drug Interaction Potentiation
• HIV Infections
• Human Immunodeficiency Virus
• Latent Tuberculosis
• Rifamycins Causing Adverse Effects in Therapeutic Use
• Tuberculosis

Intervention

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

Locations

Country	Name	City	State
United States	Thomas Jefferson University Clinical Research Unit	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Walter K. Kraft	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Adverse Event	Safety and tolerability	Days 1-24 post-dose (period 1 and 2) and 31-34 post-dose (post-study)