Clinical trial NCT03886701: Doravirine, Rifapentine and Isoniazid Interaction
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Latent Tuberculosis
Human Immunodeficiency Virus
Rifamycins Causing Adverse Effects in Therapeutic Use
Drug Interaction Potentiation
Keywords: Drug-drug interaction
Pharmacokinetics
Non-nucleoside reverse transcriptase inhibitor
NNRTI
LTBI
Antimycobacterial
Lead sponsor: Thomas Jefferson University
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2019-03-22
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Doravirine Maximum Concentration (Cmax)
timeFrame: Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
measure: Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12)
timeFrame: Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
measure: Doravirine Oral Clearance (CL/F)
timeFrame: Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
Secondary outcomes:
measure: Adverse Event
timeFrame: Days 1-24 post-dose (period 1 and 2) and 31-34 post-dose (post-study)
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Thomas Jefferson University Clinical Research Unit
state: Pennsylvania
Study officials:
affiliation: Sidney Kimmel Medical College at Thomas Jefferson University
name: Walter K Kraft, MD
role: PRINCIPAL_INVESTIGATOR
References: