Pediatric clinical trials with zidovudine (ZDV) have shown its effectiveness for the treatment of the Human Immunodeficiency Virus (HIV) disease . Clinical, virologic, and immunologic characteristics were shown to improve during the course of therapy. Unfortunately, subsequent studies in the pediatric population have been scarce and a relationship between ZDV plasma concentration and clinical efficacy has not been established. The lack of this relationship may be due to the fact that ZDV needs to be metabolized to ZDV-triphosphate (ZDV-TP) to become active, and the activation steps of the enzymatic processes are dependent on factors not related to ZDV plasma concentrations. Some of these factors include, the concentration of endogenous nucleotides competing for the virus replication with ZDV-TP formation and activation of ZDV metabolites including and the activation state of the target cells. Besides, considering the possibility of interpatient variability in the enzymatic activation processes o ZDV and AMT, it is likely that plasma ZDV concentration has little relationship with toxicity and/or antiviral activity. Therefore, intracellular measurements of ZDV metabolites may provide a better marker with respect to clinical efficacy/toxicity than plasma ZDV concentrations. The development of procedures to measure intracellular antiretroviral nucleotides in a pediatric clinical setting is of utmost importance to understand the pharmacological mechanisms of these drugs in this population. This understanding would have a great impact in the current strategy for management of HIV infection in children; however, no such information is available. Studies examining the extent of ZDV phosphorylation in the adult population are limited in their present format to pediatric studies, since they require between 15 to 75 mL of blood. This large blood volume hinders the possibilities to perform PK analysis in the pediatric population. Thus, there is a need to develop new analytical procedures that could measure intracellular levels of zidovudine and other antiretroviral drugs in the pediatric population using small blood volume samples. Our long term goal is to understand the basic pharmacological parameters that are involved with antiretroviral therapy in the pediatric population. This research project will also enhance the possibilities for underrepresented minority students to become active in a research area related to AIDS, promoting the development of new scientists and researchers in Puerto Rico.
The specific aims of the research project are: 1. to establish new methodology to decrease blood sampling volume, for the implementation of pharmacokinetic studies of ZDV-phosphorylated species in the pediatric population. These methods could be used in the future to study other antiretroviral nucleosides; 2. to establish the pharmacokinetic parameters of ZDV phosphorylated species in a pediatric population such as, in vivo ZDV-TP half-life, and develop mathematical models that could be used as tools to predict PK profiles; 3. to probe for the existing relationships between ZDV phosphorylated species pharmacological parameters and anti viral activity as measured by plasma HIV RNA-PCR (Roche); 4. to provide an opportunity for undergraduate, graduate and medical underrepresented minority students to become active in a biomedical research area that will have an impact in our society.
