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Title: Genetic determinants of key antiretroviral pharmacokinetics
Author: Siccardi, Marco
ISNI:       0000 0004 2737 2111
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2011
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Antiretroviral pharmacokinetics is one of the most important predictors of therapy efficacy and correlations between virological suppression and plasma concentrations have been described for all antiretroviral classes. Plasma concentrations are the result of absorption, distribution, metabolism and elimination (AD ME) processes which are mediated by numerous proteins in different tissues. Single nucleotide polymorphisms (SNPs) in genes encoding for individual proteins may be an important determinants drug exposure. The aim of this thesis was to characterise the role of some key SNPs determining antiretroviral plasma concentrations in order to improve the current understanding of dose-dependent efficacy and toxicity. A number of different strategies to investigate the role of genetic variability in antiretroviral exposure were developed in this thesis. The polymorphism 63396 C>T in the PXR gene, a nuclear factor regulating the expression of CYPs and transporter in hepatocytes, was proven to influence unboosted atazanavir clearance using a pharmacogenetic based population phannacokinetic model and patients with 63396TT genotype had a increment in ATV clearance of 17% (Chapter 2). In Chapter 3, the predictors of intracellular phannacokinetic of unboosted and boosted atazanavir were investigated and expression of SLC03Al, an uptake transporter expressed on PBMC was correlated with cellular accumulation of boosted and unboosted atazanavir (rho=0.706, p=0.010; rho = 0.830, P = 0.005, respectively). An in vitro in vivo extrapolation model for efavirenz was developed in Chapter 4 and the effect of CYP2B6 516 G>T on standard regimens or dose reduction was quantified. Efavirenz pharmacokinetics was predicted with good accuracy compared to available data; simulated Ctrough was 2119 ng/ml vs 1764 ng/ml, simulated Cmax was 3725 ng/ml vs 4063 ng/ml. The effect of 516G>T on simulated EFV clearance (GT = - 24% and TT = -58%) was comparable to previously published population phannacokinetic data (GT =-36%, TT =-66%). Maraviroc, a CCR5 inhibitor was identified as a substrate for SLC01B1 with a Km of 33.85 IlM and Vmax of 187.9 finol/oocyte/min and the inhibitory potential of concomitant protease inhibitors on this transporter was investigated using Xenopus laevis oocytes heterologous protein expression system (Chapter 5). Moreover the SNP SLCOIBl 521 T>C was correlated with maraviroc Ctrough in a cohort of HIV infected patients; MVC Ctrough in SLC01B1 521 heterozygote patients (TC) (n=8) was higher than in wild type homozygotes (TT) (n=22), 103 ng/ml (69 - 124) vs 46 ng/ml (28 - 66), p=0.003 (Chapter 6). The convergence of different factors under study permitted partial definition of the complex interplay in which drug-drug interactions and physical characteristics interact with genetic variability to define the phannacokinetic phenotype. These findings will help identify patients with a higher risk of achieving sub-therapeutic or potentially toxic plasma concentrations and will serve as a knowledge-base from which to grow and validate strategies for optimisation of therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available