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

Rifapentine (RPT) is a long-acting rifamycin that can be used weekly with isoniazid (INH) as
a first-line regimen in the treatment of latent tuberculosis infection (LTBI). Although this
regimen offers several potential benefits, the use of weekly RPT plus INH is not currently
recommended in adults infected with human immunodeficiency virus (HIV) on antiretroviral
therapy (ART) due to limited evidence on drug interactions with antiretrovirals (ARVs).
Dolutegravir (DTG) and darunavir boosted with cobicistat (DRV/c) comprise parts of first-line
and alternative treatment regimens, respectively, recommended for the treatment of HIV.
However, drug interactions between these ARV agents and RPT are of concern. Thus, the purpose
of this study is to determine the effects of concomitant RPT and INH administration on the
steady state PK of DTG and DRV/c.

This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to
evaluate the steady state PK of DRV/c with coadministration of once weekly RPT and INH given
at doses used to treat LTBI. 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).
Participants in Arm B will undergo periodic serial ARV PK blood draws on days 4, 14, and 19.

DTG and DRV/c PK parameters will be determined using non-compartmental methods. Cobicistat
levels will only be assessed if DRV concentrations are significantly decreased in Arm B. The
following PK parameters will be compared between phases: area under the curve over the dosing
interval, maximum plasma concentration, time to maximum plasma concentration, terminal
half-life, apparent oral clearance, and minimum plasma concentration. Adverse events will be
graded and recorded.

- INCLUSION CRITERIA:

A subject will be considered eligible for this study only if all of the following criteria
are met:

1. Ages 18 - 65 years

2. 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

3. 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)

4. Negative QuantiFERON-TB Gold test at screening

5. HIV-negative, as determined by standard serologic assays for HIV infection.

6. No laboratory evidence of active Hepatitis A, B, or C infection

7. Willing to abstain from alcohol consumption throughout the study period

8. Subject agrees to genetic testing and storage of specimens for future research

9. Negative serum or urine pregnancy test for females of child-bearing potential

10. 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:

1. Practicing absolute abstinence from sexual contact or

2. 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

- Male partner with a vasectomy

EXCLUSION CRITERIA:

A subject will be ineligible for this study if 1, or more, of the following criteria are
met:

1. Known hypersensitivity to dolutegravir, darunavir, cobicistat, rifapentine and other
rifamycin analogues, or isoniazid

2. History of type 1 hypersensitivity reaction to sulfonamides

3. History or presence of any of the following:

1. Latent or active TB infection

2. 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.),

3. Renal impairment (chronic renal insufficiency of any CKD stage, or acute renal
failure not induced by drug therapy defined as GFR < 90 ml/min)

4. Respiratory disease that is uncontrolled or requires daily treatment with
medication (asthma, chronic obstructive pulmonary disease, etc.)

5. Cardiovascular disease (hypertension [systolic blood pressure >140 mmHg or
diastolic blood pressure > 90 mmHg], heart failure, arrhythmia, etc.)

6. Metabolic disorders (diabetes mellitus, etc.)

7. Hematologic or bleeding disorders (anemia, hemophilia, serious/major bleeding
events, menorrhagia (female subjects), etc.)

8. Immunologic disorders

9. Hormonal or endocrine disorders

10. Psychiatric illness that would interfere with his or her ability to comply with
study procedures or that requires daily treatment with medication

11. Seizure disorder, with the exception of childhood febrile seizures

12. Malignancy, or

13. Any other condition that may interfere with the interpretation of the study
results, or not be in the best interest of the subject in the opinion of the
investigator

4. Fasting total cholesterol >240 mg/dL or fasting triglycerides >240 mg/dL on 2
consecutive visits

5. Fasting glucose >125 mg/dL on 2 consecutive visits

6. Current participation in an onging investigational drug protocol or use of any
investigational drug within 30 days (based on last dose received) prior to receipt of
any study drugs/medications.

7. Therapy with any prescription, over-the-counter, herbal, or holistic medications,
including hormonal contraceptives by any route, within 5 half-lives of the agent prior
to receipt of any study medications will not be permitted with the following
exception: Intermittent or short-course therapy (< 14 days) with prescription or
over-the-counter medications, herbals, or holistic medications within the screening
period prior to starting study drug may be permitted, and will be reviewed by
investigators on a case-by-case basis for potential drug interactions. Receipt of
influenza vaccination will be allowed prior to, during, and/or after the study

8. Inability to obtain venous access for sample collection

9. Inability to swallow whole capsules and/or tablets

10. Current breastfeeding

11. Drug or alcohol use that may impair safety or adherence

12. Use of nicotine-containing products, including cigarettes and chewing tobacco,
nicotine patches, gum, electronic cigarettes, etc.

13. Organ or stem cell transplant recipient

14. Uncorrected and persistent electrolyte abnormalities (e.g., potassium, magnesium, and
calcium)

15. Current alcohol abuse or alcohol dependence disorders (DSM-5 criteria)