The Influence of Ritonavir, Alone and in Combination With Lopinavir, on Fenofibric Acid Pharmacokinetics in Healthy Volunteers

Highly active antiretroviral therapy (HAART) has enhanced the life expectancy of human
immunodeficiency virus (HIV) infected patients, making HIV a manageable chronic disease for
many patients. Patients with HIV are prone to lipid abnormalities secondary to HIV infection
and antiretroviral therapy, particularly HIV protease inhibitors (PI). PI containing regimens
that contain boosting doses of ritonavir (RTV) (i.e., 100 200 mg once or twice daily) often
cause significant increases in total cholesterol, low density lipoprotein cholesterol, and
triglycerides. Therapy for isolated hypertriglyceridemia includes fibric acid derivatives,
such as gemfibrozil (GFZ) or fenofibrate; however, despite treatment with these agents,
triglyceride levels often remain elevated in HIV infected patients treated with HAART. Many
factors likely contribute to the incomplete effectiveness of fibrates in these patients. One
possible contributing factor may be a clinically significant interaction between HAART and
fibrates. We recently reported a mean 41 percent decrease in GFZ area under the curve when
administered with the PI combination lopinavir/ritonavir (LPV/r). To determine whether a
similar interaction exists with fenofibrate, this study will characterize the impact of RTV
and LPV/r on the pharmacokinetic (PK) profile of fenofibrate (Tricor formulation), after a
single 145 mg oral dose, administered to healthy volunteers. In a single sequence study
design, 13 subjects will receive a single 145 mg dose of fenofibrate on three occasions:
before and after 14 days of RTV 100 mg twice daily, and after 14 days of LPV/r 400/100 mg
twice daily. With the exclusion of the screening period, the total duration of the study will
be 48 days. Fenofibric acid (FFA) PK will be determined for all 3 sampling periods and
compared. Results from this study will inform us about a potentially clinically relevant drug
drug interaction between fenofibrate and RTV boosted PI combinations. This information may
therefore assist clinicians in choosing triglyceride lowering therapy for their HIV infected
patients.

- INCLUSION CRITERIA:

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

- Between the ages of 18 and 60 years

- Healthy according to medical history and physical examination

- Laboratory values: normal liver function tests (ALT less than or equal to 41 units/L,
AST less than or equal to 34 units/L, total bilirubin less than or equal to 1.0 mg/dL,
and direct bilirubin less than or equal to 0.2 mg/dL); serum creatinine less than or
equal to ULN; hemoglobin greater than or equal to 12 g/dL (for both males and females)

a. For patients with a history of Gilbert's Syndrome, patients with a total bilirubin
that is greater than 1.0 mg/dL will be considered eligible for study participation if
direct bilirubin is within normal limits (direct bilirubin < 0.2 mg/dL)

- Normal ECG with no history of cardiac arrhythmias or conduction abnormalities

- Females of child bearing potential who are able and willing to prevent pregnancy by

- a. practicing abstinence or

- b. using non hormonal effective methods of birth control, such as condoms or

diaphragms during the study period and for 1 month after study completion

EXCLUSION CRITERIA:

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

- Concomitant routine therapy with any prescription, over the counter, herbal, or
holistic medications, including hormonal contraceptives by any route and any
investigational drugs for 30 days prior to study participation

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

- Intermittent use of acetaminophen, non-steroidal anti-inflammatory medications
(i.e., ibuprofen), and loperamide will be allowed to be taken according to each
manufacturer s recommendations during the study, but will not be allowed on the
days of PK blood sampling

- A daily multivitamin with minerals will be allowed during the study, according to
the subject s wishes

- Inability to obtain venous access for blood sample collection

- The presence or history of any of the following:

- Diabetes mellitus (clinical diagnosis based on current guidelines)

- HIV infection

- Pulmonary disease (e.g. uncontrolled asthma, chronic obstructive pulmonary
disease, etc.)

- Cardiac disease (e.g. heart failure, history of arrhythmia, or abnormal ECG
results during screening, etc.)

- Hypertension (systolic blood pressure greater than 145 mmHG or diastolic blood
pressure greater than 90 mmHg)

- Renal disease (chronic or acute renal failure or insufficiency)

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

- Pancreatitis

- Bleeding disorders (e.g. hemophilia, gastrointestinal or intracranial bleeding)

- Organ transplant

- Seizure disorders, with the exception of childhood febrile seizures in the past

- Schizophrenia or other psychiatric illnesses that may interfere with the subject
s ability to participate in the study

- Any 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 investigators

- Positive serum or urine pregnancy test or breastfeeding female

- The presence of persistent diarrhea or malabsorption that would interfere with the
subject s ability to absorb drugs

- Drug or alcohol abuse that may impair safety or adherence

- History of intolerance or allergic reaction to LPV/r, RTV, or fenofibrate

- Fasting total cholesterol greater than 240 mg/dL or fasting triglycerides greater than
400 mg/dL

- Fasting glucose greater than 100 mg/dL

- Use of tobacco products, including cigarettes and chewing tobacco