Table 1: Prostratin progress report. The required experiments for IND submission are listed, as well as their completion status. All of these experiments must be completed and meet FDA standards before prostratin can be approved for in-human clinical trials.
Our Progress in Developing Prostratin
Significant progress has been made in the study of prostratin and its possible role as a novel anti-HIV therapeutic—work conducted by AIDS Research Alliance, as well as other laboratories. Our goal is to develop prostratin as an anti-HIV treatment that targets the viral reservoirs, and thus eradicate HIV from infected individuals.
AIDS Research Alliance has completed both in vitro and in vivo studies to examine the efficacy of prostratin to activate the HIV latent reservoir, as well as to identify potential toxicity, genotoxicity and pharmacokinetic limitations. In vitro studies examining the efficacy of prostratin were performed using both cell line models and patient samples. After six hours of treatment with prostratin in two latently infected cell lines, prostratin was able to stimulate HIV activity, as measured by reverse transcriptase activity.
CD4+ T cells were isolated from HIV+ patients on HAART and treated with prostratin. Results confirmed the ability of prostratin to stimulate HIV expression in resting T cells. In vivo pharmacology studies have also been performed to determine the single-dose range and the maximum tolerated dose. The pharmacokinetics of prostratin were determined following intravenous and oral administration. Gender differences in the distribution and metabolism of prostratin were examined, and no unique differences were observed. Genotoxicity assays were performed, and results indicate that prostratin did not induce significant genotoxicities.
The results of these studies were submitted to, and reviewed by, the U.S. Food & Drug Administration [FDA] pursuant to a pre-Investigational New Drug [pre-IND] consultation requested by AIDS Research Alliance. In response, the FDA recommended additional experiments to complete prior to IND submission. These studies include determining the effects of combining prostratin with existing anti-HIV drugs to determine if resistant virus will emerge from treatment with prostratin. Other studies will seek to determine if activation by prostratin is reversible, and whether there are any effects following administration of the drug. In addition, a series of IND-enabling pharmacology and toxicology studies of prostratin have been designed to examine toxicity and toxicokinetics following IV-infusion of prostratin.
These remaining studies must be completed before AIDS Research Alliance can submit the IND [Investigational New Drug] application to the FDA. Upon approval of prostratin as an IND, a Phase I human clinical trial will be conducted to evaluate the safety and pharmacokinetics of prostratin given via intravenous administration to HIV-infected individuals on antiretroviral therapy.
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