Studies on the mechanisms of Drug interactions of selected antiretroviral drugs with Gliclazide in animal models

Abstract

Evaluation of potent drug-drug interactions (DDIs) have become an integral approach in drug development as well as health care to provide rational therapy. This thesis concerns to explore the possible DDIs of newlineselected antiretroviral drugs (Protease Inhibitors: indinavir, ritonavir, newlineand atazanavir; Non-nucleoside reverse transcriptase inhibitors: efavirenz and nevirapine) with gliclazide (antidiabetic drug) in animal models. This study was aimed i) to investigate the safety and efficacy of newlinethe combination of selected antiretroviral drugs with gliclazide by conducting pharmacodynamic (PD) interaction studies in rats (normal and alloxan-induced diabetic) and rabbits, and pharmacokinetic (PK) newlineinteractions studies in rabbits, ii) information about the mechanism of newlineinteraction(s), if occurs and iii) to determine whether the glucose disorders associated with protease inhibitors are either class specific or drug specific. DDIs of selected antiretroviral drugs with gliclazide were evaluated i) by conducting in two dissimilar species (rodent normal and newlinediabetic rat; non-rodent - rabbit) so as to identify, validate and conclude the results with clinical perspective, ii) by extrapolating the human therapeutic oral doses of experimental drugs based on animal body surface area which underscores the clinical relevance, iii) to conduct PD and PK studies concurrently in a same rabbit group in order to establish a clear association between PD-PK and to explore the possible newlinemechanism of DDIs, iv) to determine primary PD parameters (glucose by GOD/POD method and insulin by radioimmunoassay) and secondary PD . newline Abstract newlinex newlineparameters (insulin resistance and and#946;-cell function by homeostasis model newlineassessment) at specified time intervals in order to emphasize the clinical newlinerelevance considering glucose-insulin homeostasis, and v) to conduct newlinesingle- and multiple-dose PK/PD interaction studies in order