Pharmacokinetic Interactions With Prednisolone in Healthy Volunteers and HIV-infected Patients Receiving Single-Dose Prednisone

• INCLUSION CRITERIA:

HIV-negative Healthy Subjects:

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.

HIV-infected Volunteers:

1. HIV-infected males and females between the ages of 18 and 50 years.
2. Patients receiving a stable ARV regimen for at least 30 days that includes (1) LPV/r, (2) EFV, or (3) no ARV treatment or treatment that does not contain protease inhibitors, NNRTIs, or other medications known or suspected to alter prednisolone pharmacokinetics.
3. Patients with adequately controlled HIV disease by laboratory and physical exam (HIV-RNA less than 50,000 copies/mL, CD4+ count greater than 200 cells/mm(3), no evidence of active opportunistic infections such as pneumocystis infection, mycobacterial infection etc.)
4. Laboratory values within established guidelines for participation in clinical studies: AST less than or equal to 2X ULN; hemoglobin greater than or equal to 11 g/dL.
5. Ability to abstain from ingesting grapefruit or grapefruit juice for 3 days (2 days before, and the day of prednisone administration).
6. Negative serum pregnancy test for females of child-bearing potential.
7. Females of child-bearing potential are able and willing to practice abstinence or use non hormonal effective methods of birth control during the study.

EXCLUSION CRITERIA:

HIV-negative Healthy Subjects:

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 270 mg/dL.

HIV-infected Volunteers:

1. Concomitant routine therapy with any prescription (including hormonal contraceptives), over-the-counter, herbal, or holistic medications that are known or suspected to alter prednisolone pharmacokinetics.

   • 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 as will vitamin + mineral supplementation.
2. Inability to obtain venous access for sample collection.
3. Patients taking ARV regimens that are not consistent with the study's inclusion criteria; this includes patients taking LPV in combination with EFV or nevirapine.
4. Laboratory and/or physical evidence of any active opportunistic infection.
5. Diabetes Mellitus requiring treatment with oral medications or insulin, active tuberculosis, cardiac disease (uncontrolled hypertension and/or congestive heart failure etc.), renal disease (chronic or acute renal failure or insufficiency resulting in baseline serum creatinine greater than 1.5 X upper limit of normal), untreated/uncontrolled thyroid disease, active hepatitis, 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.
6. Clinical evidence of adrenal insufficiency, Cushing's Syndrome or any other endocrine disease.
7. 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.)
8. Vaccination within 30 days of study day 1.
9. Exposure to viral illnesses such as chicken pox or measles within 30 days of study participation.
10. Positive pregnancy test or breastfeeding female.
11. The presence of persistent diarrhea or malabsorption that would interfere with the subject's ability to absorb drugs.
12. Drug or alcohol use that may impair safety or adherence.
13. History of intolerance or allergic reaction (rash; hives; swollen lips; difficulty breathing) to corticosteroid medications (e.g. prednisone; prednisolone; methylprednisolone; dexamethasone etc.).
14. 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.).