The Interaction of Two HIV Medications With Blood Clot Medications in Healthy Volunteers

Advances in antiretroviral (ARV) pharmacotherapy have translated to increased longevity and
improved quality of life in people living with HIV; hence, elderly individuals comprise an
increasing proportion of today s HIV population. Moreover, HIV infection itself has become
recognized as a condition characterized by a hypercoaguable state and premature immunologic
aging. Potential interactions between ARVs and anticoagulant medications are of particular
concern considering that many elderly, and even non-elderly HIV patients will require
short-term or chronic anticoagulation to prevent and/or treat systemic embolism. Dabigatran,
administered as dabigatran etexilate, is an oral irreversible, competitive direct thrombin
inhibitor, which has been shown to be superior to warfarin, and non-inferior to enoxaparin,
in preventing thromboembolism in patients with atrial fibrillation and undergoing orthopedic
surgery, respectively.

While dabigatran itself is not a substrate of Permeability-glycoprotein (P-gp), its
inactivepro-drug, dabigatran etexilate, is a substrate of P-gp. Co-administration of
dabigatran etexilate with P-gp modulators has resulted in significant changes in dabigatran
exposure. The pharmacokinetic enhancers, ritonavir and cobicistat, as inhibitors of P-gp,
are expected to increase plasma concentrations of dabigatran; however, neither agent has
been studied in combination with dabigatran etexilate, to date. Hence, the purpose of this
study is to determine whether the separate co-administration of ritonavir or cobicistat with
dabigatran etexilate increases the systemic exposure of dabigatran in healthy volunteers,
and if so, whether adjusting the administration times of these medications can circumvent
this interaction.

In this open-label study, 32 healthy volunteers will be assigned to 1 of 2 groups. Group A
will consist of 16 subjects who will take 22 days of ritonavir; Group B will consist of 16
subjects who will take 22 days of cobicistat. All subjects will receive 3 separated single
doses of dabigatran etexilate. Pharmacokinetic (PK) and pharmacodynamics (PD) sampling for
dabigatran will occur on Days 0 1, Day 19 1 20, and Day 26 1 27.

The PD effects of dabigatran will be characterized via ecarin clotting time (ECT)
measurements. Dabigatran PK/PD parameters will be determined using non-compartmental methods
with the WinNonlin professional computer program (version 5.2; Pharsight Corporation,
Mountain View, CA). The following PK/PD parameters will be compared between the groups: area
under the curve from 0 to 24 hours (AUC0-24), maximum total dabigatran plasma concentration
(Cmax), area under the curve from 0 to infinity hours (AUC0- ), time to maximum plasma
concentration (tmax), terminal half-life (T (Omega)), apparent oral clearance (CL/F), area
under the effect curve from 0 to 24 hours (AUEC0-24), and the maximum effect ratio over
baseline (ERmax).

- INCLUSION CRITERIA:

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

1. Between the ages 18 70 years.

2. Judged to be healthy based on medical history, physical examination, vital signs,
12-lead ECG, and clinical laboratory tests (liver function tests [LFTs] less than or
equal to 2 times upper limit of normal [ULN], serum creatinine [sCr] less than or
equal to ULN.

3. Subject agrees to storage of specimens for future research.

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

5. For female subjects, willing to prevent pregnancy by (a) practicing abstinence or (b)
using effective non-hormonal and/or barrier methods of birth control, during the
study period.

EXCLUSION CRITERIA:

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

1. History of HIV exposure/infection, as determined by positive ELISA/ Western Blot.

2. History or presence of any of the following:

- gastrointestinal disease, that is uncontrolled or requires daily treatment with
medication (pancreatitis, peptic ulcer disease, etc.)

- hepatitis (as assessed by patient interview) or hepatic impairment

- renal impairment (chronic or acute renal failure or insufficiency)

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

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

- metabolic disorders (diabetes mellitus, etc.)

- immunologic disorders

- hormonal disorders

- psychiatric illness, that would interfere with his or her ability to comply with
study procedures or that requires daily treatment with medication

- seizure disorder, with the exception of childhood febrile seizures

- malignancy, or P-3 Pharmacoenhancers & Pradaxa, a P-gp Substrate 26

- 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.

3. History or presence of the following:

- bleeding/hematologic disorders (hemophilia, etc.)

- serious/major bleeding event (intracranial, gastrointestinal, as assessed by
patient interview)

c. current increased risk of bleeding (as indicated by aPTT >1.5 times ULN],
platelets, PLT, <150,000/mm3, or Hgb <11 g/dL)

d. for female subjects, menorrhagia

4. Planned invasive or surgical procedure within (prior to, or following) 28 days of
study participation.

5. Fasting total cholesterol >270 mg/dL or fasting triglycerides >270 mg/dL.

6. Fasting glucose >125 mg/dL.

7. Concomitant routine therapy with any prescription, over-the-counter, herbal, or
holistic medications, including hormonal contraceptives by any route, or any
investigational drugs for 30 days prior to receipt of any study medications (Day 0).

1. Concomitant therapy (chronic or intermittent) with any prescription,
over-the-counter, herbal, or holistic medications will not be allowed during the
study duration

2. Intermittent use of acetaminophen and loperamide will be allowed to have been
taken, according to each manufacturer s recommendations, within 30 days prior to
study participation

3. Intermittent use of acetaminophen, loperamide, and/or an antiemetic (as approved
by the Principal Investigator) will be allowed to be taken according to each
manufacturer s recommendations during the study. As P-gp substrates, loperamide
and certain anti-emetics (i.e. ondansetron), should not be taken on the days of
pharmacokinetic blood sampling

4. A daily multivitamin with minerals will be allowed during the study

5. Receipt of influenza vaccination will be allowed prior, during,

and/or after the study

6. Use of topical medications that are not significantly absorbed systemically will
be allowed if approved by the Principal Investigator

8. Inability to obtain venous access for sample collection.

9. Inability to swallow whole capsules and/or tablets.

10. Positive serum or urine pregnancy test or breastfeeding female.

11. The presence of persistent diarrhea or malabsorption that could interferewith the
subject s ability to absorb drugs.

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

13. Use of nicotine-containing tobacco products, including cigarettes and chewing
tobacco.

14. History of intolerance or allergic reaction (rash; hives; swollen lips;difficulty
breathing) to DE, RTV, or COBI.

15. Organ transplant recipient.