This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: There has been a growing change in the epidemiology of HIV-1 infection world-wide with a steady increase in the rates of new infections among women. Whereas relatively few women were diagnosed with AIDS early in the epidemic, current data from the Centers for Disease Control and Prevention show that the proportion of AIDS cases reported among women in the United States increased from 8% in 1986 to 26% in 2001. HIV/AIDS seems to affect men and women differently, although there is no consensus on the mechanism of these effects at the cellular level. The majority of studies suggest that cytochrome P450 3A4 activity is higher in women when compared to men, whereas the activity of many other enzyme systems involved in drug metabolism may be higher in men. It has also been suggested that drug transport proteins, like P-glycoprotein, might play a role. These differences may have important consequences for virologic outcomes and drug toxicity. Antiretroviral drugs have a fairly narrow therapeutic index; therefore, defining those populations with increased or decreased clearance of these drugs could lead to improved tolerability and efficacy. Although there are few published studies of sex-based differences in antiretroviral pharmacokinetics, there is a growing awareness that the under-representation of women in clinical trials, and in particular Phase I studies, may lead to an incomplete understanding of the optimal dosing of drugs. The currently available data illustrate the need for definitive information on the relationship between sex and antiretroviral pharmacokinetics (PK). This study, which seeks to examine the sex differences in the descriptive PK of Lopinavir (LPV) is a logical first step in this regard. LPV is a potent inhibitor of HIV-1 protease. It prevents cleavage of the Gag-Pol polyprotein resulting in the production of immature, non-infectious viral particles. When co-formulated with LPV, Ritonavir (RTV) inhibits the cytochrome P450 3A-mediated metabolism of LPV, thereby providing increased plasma levels of LPV. LPV/RTV has been evaluated and approved by the Food and Drug Administration (FDA) for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. LPV/RTV (in combination with other antiretroviral agents) has been shown to be effective in suppressing viral replication in both anti-retroviral naive and experienced patients. There are no definitive data on the PK parameter that best correlates with long-term virologic response to therapy. It is generally believed, however, that the Cmin is the most important parameter related to sustained suppression of viral replication. The Cmax may provide useful information on the potential for toxicity. The parameters of interest in our study are maximum concentration, minimum concentration, and area under the concentration-time curve (AUC). Our study plan is unique in several ways. It will be the first large prospective study of sex differences in the PK of LPV/RTV conducted in HIV-1-infected individuals. There will be intensive PK sampling and measures incorporated to reduce potential confounders due to differences in rate of compliance among the different groups. In addition, the effect of race/ethnicity on antiretroviral PK has the potential of being a confounder in the current study. In order to address this, we propose to stratify both male and female groups by race/ethnicity. We have opted to standardize the background regimen for subjects entering the study. Subjects on LPV/RTV with one or more of the following: nucleoside reverse transcriptase inhibitors (NRTIs), Tenofivir (TDF) and Enfuvirtide, will be eligible to be included in the study. There is insufficient evidence to conclude that there is any clinically significant PK interaction between LPV and TDF that results in a decrease in LPV concentrations. On the contrary, there are data from a well-designed PK study that concludes that there is no significant adverse PK interaction between these two drugs that lowers LPV concentrations. We also intend to enroll enough women to demonstrate a difference in these PK parameters if indeed a difference of 30% or larger exists. We intend to use the data collected on completion of the study as a basis for proposing larger studies with additional drugs specifically looking at potential differences in efficacy and toxicity between the sexes, and to stimulate study into the mechanistic basis of this difference. We hypothesize that women achieve higher LPV drug levels than do men on similar doses of LPV/RTV. Experimental Design: This study is a prospective evaluation of 78 HIV-1-infected subjects designed to determine the PK of LPV in men and women.
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