Latent Tuberculosis, Human Immunodeficiency Virus, Rifamycins Causing Adverse Effects in Therapeutic Use, Drug Interaction Potentiation
Conditions
Keywords
Drug-drug interaction, Pharmacokinetics, Non-nucleoside reverse transcriptase inhibitor, NNRTI, LTBI, Antimycobacterial
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.
Interventions
DRUGDoravirine (DOR)
Non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection in adults in combination with other antiretroviral agents.
Rifamycin anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection.
DRUGIsoniazid (INH)
Anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection.
Sponsors
Merck Sharp & Dohme LLC
Walter K. Kraft
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Doravirine Maximum Concentration (Cmax) | Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | Doravirine maximum observed concentration during the dosing interval |
| Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12) | 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 time curve derived from plasma sampling during one dosing interval |
| Doravirine Oral Clearance (CL/F) | Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | Doravirine apparent oral clearance derived from plasma sampling |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Event | Days 1-24 post-dose (period 1 and 2) and 31-34 post-dose (post-study) | Safety and tolerability |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Study Particpants Eleven healthy volunteers enrolled into the study. | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Study Particpants |
|---|---|
| Age, Continuous | 50 years |
| Race/Ethnicity, Customized Black or African American | 8 Participants |
| Race/Ethnicity, Customized White | 3 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 10 Participants |
| Weight | 92.9 Kilogram STANDARD_DEVIATION 11.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 4 / 11 | 6 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
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
Time frame: Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Period 1 | Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12) | 17.3 hr x ug/mL |
| Period 2 | Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12) | 12.3 hr x ug/mL |
Primary
Doravirine Maximum Concentration (Cmax)
Doravirine maximum observed concentration during the dosing interval
Time frame: Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Period 1 | Doravirine Maximum Concentration (Cmax) | 1.7 ug/mL |
| Period 2 | Doravirine Maximum Concentration (Cmax) | 1.3 ug/mL |
Primary
Doravirine Oral Clearance (CL/F)
Doravirine apparent oral clearance derived from plasma sampling
Time frame: Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1 | Doravirine Oral Clearance (CL/F) | 5.9 L/hr | Geometric Coefficient of Variation 24 |
| Period 2 | Doravirine Oral Clearance (CL/F) | 8.4 L/hr | Geometric Coefficient of Variation 26.1 |
Secondary
Adverse Event
Safety and tolerability
Time frame: Days 1-24 post-dose (period 1 and 2) and 31-34 post-dose (post-study)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Period 1 | Adverse Event | Nausea/vomiting | 1 participants |
| Period 1 | Adverse Event | Dysuria | 0 participants |
| Period 1 | Adverse Event | Fever | 0 participants |
| Period 1 | Adverse Event | Headache | 0 participants |
| Period 1 | Adverse Event | Chills | 0 participants |
| Period 1 | Adverse Event | Catheter site pain and redness | 3 participants |
| Period 2 | Adverse Event | Chills | 1 participants |
| Period 2 | Adverse Event | Nausea/vomiting | 0 participants |
| Period 2 | Adverse Event | Headache | 1 participants |
| Period 2 | Adverse Event | Dysuria | 1 participants |
| Period 2 | Adverse Event | Catheter site pain and redness | 2 participants |
| Period 2 | Adverse Event | Fever | 1 participants |