Protocol Number: 04-CC-0040

Title:

Prednisolone Pharmacokinetics in the Presence and Absence of Ritonavir after Oral Prednisolone Administration to Healthy Volunteers

Number:

04-CC-0040

Summary:

This study will evaluate the impact of the HIV protease inhibitor ritonavir on the pharmacokinetics-that is, the interaction of the medication and the body-of prednisolone after prednisone is given to healthy volunteers. Prednisone, an agent known as a corticosteroid, or steroid hormone, is converted by the body into prednisolone. Ritonavir is an HIV medication that fights the virus by blocking its ability to reproduce. Sometimes it increases the blood levels of other drugs given at the same time, and it is possible that ritonavir increases the blood levels of prednisolone and those of other medications. Results from the study will provide information on whether prednisone and ritonavir interact in a potentially harmful way. The MDR1 genotype, that is, part of a person's genetic constitution, may influence how prednisolone behaves.

Patients 18 to 50 years of age who are in good health, who not have HIV, and who do not smoke may be eligible for this study. There will be 10 participants and another 5 later who will be control subjects. Those in the control group will take only prednisone, not ritonavir.

Participants will undergo the following tests and procedures:

-Medical history and physical examination.

-Collection of blood and urine to assess general health.

-Collection of blood to examine markers on white blood cells and to determine the kind of MDR1 gene was inherited.

-HIV test.

The screening visit will take about 3 to 4 hours, and the study will take about 28 to 49 days. For 3 study days, participants will remain in the clinic for 12 hours, On Study Day 1, patients will be asked to not eat or drink anything besides water before coming to the clinic. Blood samples will be collected to measure prednisolone concentration as well as osteocalcin, a blood protein involved in bone formation. Blood tests will also allow a look at the surfaces of some white blood cells. Patients will receive a breakfast along with 20 mg of prednisone. Urine samples will be collected also. Then patients will be dismissed and asked to collect urine samples and return them on the following morning, Study Day 2. At that time there will additional blood collection. Patients will begin taking ritonavir between 7 and 28 days after the first dose of prednisone, at a dose of 200 mg (two 100 mg capsules) twice daily with food, to continue for 15 days. On the 4th and 14th days of their taking ritonavir, patients will be asked to visit the clinic in the morning for a blood to measure ritonavir in the blood and to take a single 20-mg dose of prednisone along with the ritonavir. Both medications will be taken with breakfast. Blood and urine levels of prednisolone will also be measured. On the 15th day of ritonavir dosing, there will be another blood collection for routine lab tests, as well as studies on blood cells and osteocalcin.

Sponsoring Institute:

Warren G. Magnuson Clinical Center (CC)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

1.) Males and females between the ages of 18 and 50 years.

2.) Healthy by medical history and physical exam

3.) Laboratory values within established guidelines for participation in clinical studies: AST less than or equal to 2 X ULN; Serum creatinine less than or equal to ULN; hemoglobin greater than or equal to 11 g/dL.

4.) Ability to abstain from ingesting grapefruit or grapefruit juice during the study period..

5.) Negative serum pregnancy test for females of child-bearing potential.

6.) Females of child-bearing potential are able and willing to practice abstinence or use non-hormonal effective methods of birth control during the study.

7.) Non-smoker for at least 6 weeks prior to study participation.

EXCLUSION CRITERIA:

1.) Concomitant routine therapy with any prescription, over-the-counter, herbal, or holistic medications, including oral contraceptives for 30 days prior to study participation.

-Subjects must be off oral contraceptives for at least 30 days prior to study day 1.

-Intermittent (PRN) use of acetaminophen and non-steroidal anti-inflammatory medications (i.e. ibuprofen) will be allowed during the study; these medications should not be taken on days of prednisone administration (study days 1, 10, and 20).

-Subjects will be allowed to take a multivitamin with minerals, or equivalent, once daily if they desire to do so.

2.) Inability to obtain venous access for sample collection.

3.) Presence of Diabetes Mellitus, Human immunodeficiency virus (HIV) infection, active tuberculosis, cardiac disease (hypertension; congestive heart failure etc.), renal disease (chronic or acute renal failure or insufficiency), thyroid disease, hepatitis, osteoporosis, osteonecrosis, respiratory disease (asthma requiring chronic treatment; chronic obstructive pulmonary disease), myasthenia gravis, glaucoma, peptic ulcer disease requiring treatment, history of psychiatric illness (other than mild depression or anxiety) or 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.) Clinical evidence of adrenal insufficiency, Cushing's Syndrome or any other endocrine disease.

5.) Any clinical or laboratory evidence of active infection (persistent fevers, night sweats, nausea, vomiting, diarrhea, chronic cough, WBC greater than the upper limit of normal.)

6.) Vaccination within 30 days of study day 1.

7.) Exposure to viral illnesses such as chicken pox or measles within 30 days of study participation.

8.) Positive pregnancy test or breastfeeding female.

9.) The presence of persistent diarrhea or malabsorption that would interfere with the subject's ability to absorb drugs.

10.) Drug or alcohol use that may impair safety or adherence.

11.) History of intolerance or allergic reaction (rash; hives; swollen lips; difficulty breathing) to corticosteroid medications (e.g. prednisone; prednisolone; methylprednisolone; dexamethasone etc.) or protease inhibitors (ritonavir; lopinavir; amprenavir; indinavir; nelfinavir; saquinavir; atazanavir).

12.) Inability or unwillingness of females of child-bearing potential to use a non-hormonal (barrier) method of contraception throughout the study (e.g. condom; diaphragm etc.).

13.) Non-fasting total cholesterol or triglycerides greater than or equal to 27

Special Instructions: Currently Not Provided

Keywords:

HIV

Osteonecrosis

Drug Interaction

P-Glycoprotein

Cytochrome P 450

Healthy Volunteer

HV

Recruitment Keywords:

None

Conditions:

Healthy

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med. 2001 Mar 29;344(13):984-96. Review.

Miller KD, Masur H, Jones EC, Joe GO, Rick ME, Kelly GG, Mican JM, Liu S, Gerber LH, Blackwelder WC, Falloon J, Davey RT, Polis MA, Walker RE, Lane HC, Kovacs JA. High prevalence of osteonecrosis of the femoral head in HIV-infected adults.

Ann Intern Med. 2002 Jul 2;137(1):17-25.

Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ Jr, Feinberg JE, Balfour HH Jr, Deyton LR, Chodakewitz JA, Fischl MA. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997 Sep 11;337(11):725-33.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
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