Brief Title
The Effect of Efavirenz and Nelfinavir on the Blood Levels of Certain Lipid-Lowering Drugs
Official Title
The Effect of Efavirenz and Nelfinavir on the Pharmacokinetics of Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors
Brief Summary
The purpose of this study is to find out whether certain anti-HIV drugs (efavirenz [EFV] and
nelfinavir [NFV]) affect the amount of certain fat-lowering drugs (atorvastatin, pravastatin,
and simvastatin) in the blood.
Protease inhibitors (PIs), a type of anti-HIV drug, are known to cause increased lipids
(fats) in the blood of HIV-infected patients. EFV also is known to increase blood fats.
HIV-infected patients who take PIs and/or EFV may need to take fat-lowering drugs to correct
this problem. So it is important to look at possible drug interactions when these drugs are
taken together. This study will see if taking EFV or NFV, a protease inhibitor, affects the
blood level of simvastatin, atorvastatin, or pravastatin (all fat-lowering drugs). To obtain
results more quickly, the study population will be healthy HIV-negative volunteers.
Detailed Description
Abnormalities in lipid metabolism are a recognized side effect of protease inhibitor (PI)
therapy in HIV-infected patients. EFV also is known to increase plasma cholesterol. In an
attempt to normalize serum lipids in HIV-infected patients on PIs and/or EFV,
Hydroxymethylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (also known as statins) may
be prescribed. Therefore, it is important to study how PIs and EFV affect the PK of
concurrently-administered statins. Many of the statins utilize the cytochrome P450 (CYP) 3A4
enzyme for metabolism. In addition, atorvastatin and simvastatin have active metabolites,
generated via CYP3A4, that contribute to the drugs' lipid-lowering activity and probably to
their toxicity. Pravastatin is not metabolized by CYP3A4 but is inactivated by conjugation,
non-CYP3A4-induced hydroxylation, and renal excretion. NFV, the most commonly used PI, is an
inhibitor of CYP3A4 and an inducer of other CYPs and conjugative pathways. EFV is a mixed
CYP3A4 inhibitor and inducer. This study examines the effect of NFV on the PK of pravastatin
and the effect of EFV on the PK of simvastatin, atorvastatin, and pravastatin. As EFV with
pravastatin is expected to be a common drug combination during the treatment of HIV
infection, it should be explored further, even though drug interactions are not expected. To
expedite this study, the study population is comprised of healthy control volunteers.
Volunteers are assigned to 1 of 4 groups. Volunteers in Groups A, B, and C take a statin
(simvastatin, atorvastatin, or pravastatin, respectively) on Days 0 to 3. After Day 3, the
statin is stopped and EFV is begun. Volunteers take EFV until Day 14 and the statin and EFV
together from Days 15 to 18. Volunteers in Group D take pravastatin on Days 0 to 3, NFV on
Days 4 to 12, and pravastatin and NFV together on Days 13 to 16. Fasting lipid profiles are
performed on Days 0, 4, 15, and 19 for Groups A, B, and C, and on Days 0, 3, 13, and 16 for
Group D. PK sampling is performed on Days 3, 14, and 18 for Groups A, B, and C (requiring an
overnight stay), and on Days 3 and 16 for Group D. Volunteers receive monetary compensation
for participation in this study.
Study Phase
Phase 1
Study Type
Interventional
Condition
HIV Infections
Intervention
Pravastatin sodium
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
56
Eligibility Criteria
Inclusion Criteria
Volunteers may be eligible for this study if they:
- Are HIV-negative.
- Are 18 to 60 years old.
- Weigh at least 50 kg (110 lbs) and are within 30 percent of their ideal body weight.
- Cannot have children (have reached menopause [change of life] for at least 24 straight
months or have had a hysterectomy), if female and enrolling to Group A, B, or C.
- Have a negative pregnancy test within 14 days before study entry and within 24 hours
before starting the study drugs, if female, able to have children, and enrolling to
Group D.
- Agree to avoid trying to become pregnant or causing someone to become pregnant. Agree
not to donate sperm or participate in other fertilization procedures. If participating
in sexual activity that could lead to pregnancy, the study volunteer and/or partner
must use 2 reliable methods of birth control at the same time, while taking study
drugs, and for 6 weeks after stopping the drugs. Male volunteers are allowed to be
sexually active without the use of birth control if they have had a successful
vasectomy or are sterile.
Exclusion Criteria
Volunteers will not be eligible for this study if they:
- Have or have had heart, kidney, blood, nerve, digestive, mental, hormonal, or immune
system diseases. These include high blood pressure, blocked arteries, arthritis,
diabetes, stomach or intestinal problems, depression, and past use of antidepressant
drugs.
- Are pregnant or breast-feeding.
- Have used experimental, prescription, or over-the-counter drugs within 14 days before
study entry, except for aspirin (ASA), acetaminophen (Tylenol), diphenhydramine
(Benadryl), daily multivitamins, mineral supplements, birth control pills or implants,
and hormone replacement therapy for women who have reached menopause.
- Are allergic to study drugs or their ingredients.
- Abuse drugs or alcohol.
- Have a medical condition that, in the opinion of the investigator, would interfere
with their participation in the study.
- Have participated in any experimental drug study within 30 days before study entry.
- Are not able to keep their usual diet during the study or are unable to write down
their food intake before the study visits.
- Have an abnormal urine test result, e.g., urinary tract infection, kidney disease, or
kidney stones.
Gender
All
Ages
18 Years - 60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Contacts
John Gerber, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00017758
Organization ID
ACTG A5108
Secondary IDs
AACTG A5108
Study Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor
John Gerber, Study Chair,
Verification Date
February 2004