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. Despite the hypothesized interaction between protease inhibitors and corticosteroids, drug interactions between agents from these pharmacologic classes have not been formally investigated. The purpose of this study is to determine the impact of the HIV protease inhibitor ritonavir on the pharmacokinetics of prednisolone after administration of oral prednisone to healthy volunteers. Ten 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. To assess subject adherence with the study protocol, pre-dose blood samples for determination of ritonavir concentrations will be collected during the study; pill counts will also be conducted. Prednisolone and ritonavir concentrations will be determined by validated high performance chromatographic methods. Non-compartmental methods will be used to characterize prednisolone pharmacokinetics before and after ritonavir. Pharmacokinetic parameters 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 an HIV protease inhibitor (ritonavir) on the pharmacokinetics of a corticosteroid medication (prednisolone). This study was reviewed by the NIAID IRB in August 2003. IRB Approval is expected in September 2003 and subject enrollment will likley begin in October 2003.

National Institute of Health (NIH)
Clinical Center (CLC)
Intramural Research (Z01)
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Pharmacy Review Committee (PHAR)
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United States
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Busse, Kristin H; Formentini, Elizabeth; Alfaro, Raul M et al. (2008) Influence of antiretroviral drugs on the pharmacokinetics of prednisolone in HIV-infected individuals. J Acquir Immune Defic Syndr 48:561-6
Penzak, Scott R; Formentini, Elizabeth; Alfaro, Raul M et al. (2005) Prednisolone pharmacokinetics in the presence and absence of ritonavir after oral prednisone administration to healthy volunteers. J Acquir Immune Defic Syndr 40:573-80