Efavirenz displays many desirable pharmacokinetic properties such as a long half-life allowing once daily dosing and potency against HIV. Despite these favourable properties efavirenz-containing therapy is associated with the development of central nervous system (CNS) toxicities. Current investigations indicate that high plasma concentrations of efavirenz play a putative role in the development of CNS side effects, but there is a current paucity of data relating to the underlying mechanisms of

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... toxicity. Various nanotechnologies have been explored in attempts to mitigate some of the limitations with efavirenz. While there has been progress in increasing the bioavailability of efavirenz there has been no attempt to assess the impact of increased exposure to efavirenz on CNS toxicity. The body of work presented in this thesis aimed firstly to investigate the underlying mechanism of efavirenz CNS toxicity and secondly to assess uptake and CNS toxicity of efavirenz and a novel solid drug nanoformulation (SDN) of efavirenz. The work presented in this thesis utilised a variety of in vitro, in vivo and in silico methodologies. Chapter 2 utilised allelic discrimination polymerase chain reaction in order to investigate the association of single nucleotide polymorphism (SNPs) in the gamma aminobutyric acid receptor with early treatment discontinuation of efavirenz. In order to assess the effects of SDN efavirenz on the occurrence of CNS toxicities, an in vivo model of anxiety (elevated plus maze) was employed (chapter 3). Chapter 4 detailed the development of a robust and sensitive liquid chromatography tandem mass spectrometer assay for the detection of efavirenz in multiple matrices. The uptake of efavirenz and SDN efavirenz in the CNS was investigated utilising cellular uptake and inhibition studies (chapter 5). Physiologically based pharmacokinetic (PBPK) simulations were used to investigate the distribution of efavirenz in plasma, cerebrospinal fluid (CSF) and brain tissue (chapter 6). Despite an initial trend with Rs [...]