CONCENTRATION-CONTROLLED ANTIRETROVIRAL THERAPY

Treatment of human immunodeficiency virus infection (HIV-1) with
antiretroviral drugs represents an essential component of strategies to
modify the course of HIV disease for the foreseeable future. Zidovudine
(ZDV) has been shown to reduce morbidity and prolong survival time in
HIV-infected persons. Currently, a standard fixed dose (500-600 mg/day)
of ZDV is recommended for all adults but it is not known whether ZDV
dosing should be based on body weight. Furthermore, we do not know if
the dosage regimen should be individualized based on patient-specific
characteristics of ZDV absorption, distribution, metabolism, and
elimination, and whether this approach would result in greater efficacy
or fewer adverse reactions. The long-term goal of this project is to
determine the optimal dosing strategy for antiretroviral agents that
ensures maximum benefit. We will begin these investigations with ZDV
because it represents the "gold-standard" of therapy. The specific aims
of this project are: first, to demonstrate, using minimally invasive
strategies, that concentration-controlled ZDV therapy, contrasted to the
standard fixed-dose approach, can achieve and maintain a target level of
exposure and reduce the variability associated with steady-state
concentrations and area-under-the-curve; second, determine the safety and
antiviral activity of concentration-controlled vs standard ZDV therapy
and employ pharmacodynamic modeling techniques to develop quantitative
concentration and effect relationships; and finally, to develop and
evaluate predictive models for other antiretroviral agents, such as
didanosine. We propose to conduct a randomized, crossover, open-label,
outpatient study in 30 HIV-infected individuals using two different ZDV
regimens: a fixed dose of 5OO mg/day, and a concentration-controlled
regimen designed to maintain a steady-state concentration of O.7 microM.
The total duration of this study will be 24 weeks. Participants will be
randomized to either the concentration-controlled or standard ZDV regimen
for the first 12 weeks, and then crossed over to the alternative regimen
for an additional 12 weeks. Study participants will be closely monitored
for safety, tolerance, ZDV serum concentrations, virologic and
immunologic parameters, opportunistic infections, and progression of HIV-
1 disease. Data analysis will compare the two ZDV dosing regimens in
terms of concentrations achieved, safety, antiviral efficacy, and
pharmacodynamic relationships. The work proposed in this application
will answer several questions concerning our use and understanding of ZDV
therapy; however, the knowledge gained and the methods used will be
applicable to other antiretroviral drugs. This study represents a
significant step in learning whether we can improve upon the rather
primitive "treat everyone the same" dosing strategies currently used for
nucleoside antiretroviral drugs.