Pharmacokinetic Interactions With Prednisolone in Healthy Volunteers and HIV-infected Patients Receiving Single-Dose Prednisone
Condition: Healthy
Study type: Observational

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.
    

Detailed description: 
      Corticosteroid administration has been associated with a variety of toxicities, including
      osteonecrosis and Cushing's Syndrome, in patients with HIV infection. The prevalence of these
      toxicities has led to speculation that protease inhibitors impair the cytochrome P450 (CYP)
      3A4-mediated metabolism of corticosteroids leading to an increase in their systemic exposure
      and toxicity. Conversely, reduced corticosteroid exposure may be expected when these drugs
      are coadministrated with CYP3A4 inducers such as the non-nucleoside reverse transcriptase
      inhibitor (NNRTI) efavirenz. Despite the hypothesized interaction between antiretroviral
      medications and corticosteroids, drug interactions between agents from these classes have not
      been formally investigated. The objectives of this study are (1) to determine the impact of
      the HIV protease inhibitor ritonavir on the pharmacokinetics of prednisolone after
      administration of oral prednisone to healthy volunteers and (2) to determine the respective
      influences of chronic dosing with lopinavir-ritonavir (LPV/r) and efavirenz (EFV) on
      prednisolone pharmacokinetics in HIV+ individuals taking a single dose of prednisone. For the
      HIV-negative healthy volunteer portion of the study, 10 HIV-negative study subjects will
      receive a single 20 mg dose of prednisone before, and after 3 and 14 days of ritonavir
      exposure at 200 mg twice daily. Blood and urine will be collected over 24 hrs after
      prednisone administration to determine prednisolone pharmacokinetics and renal elimination.
      Blood will also be collected for determination of MDR1 genotype, which may influence
      prednisolone disposition. For the portion of the study conducted in HIV-infected volunteers,
      3 groups of 10 subjects will be recruited to receive a single 20 mg dose of prednisone
      followed by serial blood sampling for prednisolone concentrations. The 3 groups will consist
      of (1) individuals receiving and HIV treatment regimen (for at least 30 days) that includes
      LPV/r (2) individuals receiving an HIV treatment regimen (for at least 30 days) that includes
      EFV and (3) individual receiving no antiretroviral treatment or treatment devoid of HIV
      protease inhibitors or NNRTIs. Prednisolone concentrations will be determined by validated
      high performance chromatographic methods. Non-compartmental methods will be used to
      characterize prednisolone pharmacokinetics in all study groups. Pharmacokinetic parameter
      values will be compared using ANOVA with post-hoc testing. Geometric mean data with 90%
      confidence intervals will be reported. This study will characterize, for the first time, the
      influence of antiretroviral medications on the pharmacokinetics of a corticosteroid
      medication (prednisolone).
    

Keywords: HIV; Osteonecrosis; Drug Interaction; P-Glycoprotein; Cytochrome P 450; Healthy Volunteer; HV