von Kleist, Max and Huisinga, Wilhelm (2009) Pharmacokinetic-Pharmacodynamic relationship of NRTIs and its connection to viral escape: An example based on Zidovudine. European Journal of Pharmaceutical Sciences, 36 (4-5). pp. 535-543. ISSN 0928-0987

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Abstract

In HIV disease, the mechanisms of drug-resistance are only poorly understood. Incomplete suppression of HIV by antiretroviral agents is suspected to be a main reason. The objective of this in silico study is to elucidate the pharmacokinetic origins of incomplete viral suppression, exemplfied for zidovudine (AZT) as a representative of the key class of nucleoside reverse transcriptase inhibitors (NRTIs). AZT, like other NRTIs, exerts its main action through its intracellular triphoshate (AZT-TP) by competition with natural thymidine triphosphate. We developed a physiologically based pharmacokinetic (PBPK) model describing the intracellular pharmacokinetics of AZT anabolites and subsequently established the pharmacokinetic-pharmacodynamic relationship. The PBPK model has been validated against clinical data of different dosing schemes. We reduced the PBPK model to derive a simple three- compartment model for AZT and AZT-TP that can readily be used in population analysis of clinical trials. A novel machanistic, and for NRTIs generic effect model has been developed that incorporates the primary effect of AZT-TP and potential secondary effect of zidovudine monophosphate. The proposed models were used to analyze the e±cacy and potential toxicity of different dosing schemes for AZT. Based on the mechanism of action of NRTIs, we found that drug heterogeneities due to temporal fluctuations can create a major window of unsuppressed viral replication. For AZT, this window was most pronounced for a 600mg/once daily dosing scheme, in which insu±cient viral suppression was observed for almost half the dosing period.

Item Type:	Article
Keywords:	Reverse transcription; Intra-cellular phosphorylation; PBMC; HIV; CD4; Pharmacodynamics; Hamilaton Institute.
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Hamilton Institute
Item ID:	1848
Identification Number:	https://doi.org/10.1016/j.ejps.2008.12.010
Depositing User:	Hamilton Editor
Date Deposited:	16 Feb 2010 10:48
Journal or Publication Title:	European Journal of Pharmaceutical Sciences
Publisher:	Elsevier
Refereed:	No
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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