Lay summary
Lead:Clinical pharmacokinetic and pharmacogenetic research efforts have to be pursued in HIV therapeutics because of the prevalence of toxicity, the life-long nature of treatment, and the complexity inherent to multidrug therapy.Abstract:The proposed research project aims at increasing the current understanding of the complex gene-environmental interplay influencing toxicity and efficacy of antiretroviral treatment at the patient and the population levels, thus offering new possibilities for improving the long term tolerability and response to antiretroviral treatments. Drug pharmacokinetics is a phenotypic trait influenced by complex genetic and non-genetic factors affecting drug transport and metabolism. Pharmacogenetics aim at determining patients genetic predisposition influencing drug exposure, toxicity and clinical response. However, current approaches in pharmacokinetics have focused almost exclusively on the parent drug concentrations while current approaches in pharmacogenetics have examined one or few candidate genes for a limited number of genes variants. Aim:This current research project addresses the Pharmacology and Pharmacogenetics of new antiretroviral drugs via the a) Integration of drug metabolite profiling and pharmacogenetics analysis of all pathways likely to be implicated in the absorption, distribution, metabolism and excretion of antiretroviral agents b) Development of population pharmacokinetic/pharmacogenetics models. c) Translation to clinical studies aiming at validating the usefulness of new pharmacokinetic and pharmacogenetic tools. Significance:Pharmacogenetics is likely to have a profound impact on our current understanding of the variability observed in drug exposure (pharmacokinetics), clinical response and toxicity (pharmacodynamics) of antiretroviral agents. Pharmacogenetic tests are being developed in sight of determining genetic predispositions to toxicity and unsatisfactory clinical response, thereby identifying the antiretroviral regimen most likely to be effective and with limited drug toxicity in a given patient.