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Understanding Disposition of Efavirenz and Application in Solid Drug Nanoparticle Development
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Dissertation
Understanding Disposition of Efavirenz and Application in Solid Drug Nanoparticle Development
2015
Overview
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 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 Rs211014 and Rs6556547 (univariate analysis) of the training cohort, these SNPs were not found to be significant in the multivariate analysis or in either analysis of the test cohort. Following multiple doses rats treated with efavirenz, but not SDN efavirenz, exhibited anxiety-like behaviour in the EPM. The profile of changes indicated some clear behavioural effects that are likely to be linked to drug-related CNS effects. In particular, a tendency of efavirenz to increase time spent on the central platform may be indicative of anxiogenesis. Cellular accumulation of efavirenz was reduced significantly by montelukast and amantadine, with the reduction in accumulation by prazosin bordering on significance (indicating efavirenz may be a substrate for OCT1 and an SLCO transporter). Additionally, cellular accumulation of SDN efavirenz particles was reduced by dynasore, indicating dynamin-mediated uptake. PBPK simulations predicted efavirenz accumulation in brain tissue, with a tissue to plasma ratio 15.8. The natural occurrence of conditions such as depression involves a complex interplay of factors influencing neurotransmission. This makes identifying single predictors of efavirenz CNS toxicity more difficult. The data presented in this thesis may be built upon to understand the mechanisms governing efavirenz disposition in the CNS and factors influencing the occurrence of CNS toxicity.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798607339951
