Pharmacokinetic-pharmacodynamic relationship of NRTIs and its connection to viral escape: an example based on zidovudine

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Max von Kleist, Wilhelm Huisinga

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, exemplified 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 intra-cellular triphoshate (AZT-TP) by competition with natural thymidine triphosphate. We developed a physiologically based pharmacokinetic (PBPK) model describing the intra-cellular 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 efficacy and po...Continue Reading

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Citations

Apr 3, 2010·PLoS Computational Biology·Max von KleistWilhelm Huisinga
Jan 23, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Sulav Duwal, Max von Kleist
Nov 17, 2009·Advanced Drug Delivery Reviews·José das NevesBruno Sarmento
Nov 13, 2014·CPT: Pharmacometrics & Systems Pharmacology·K MadrasiA Chaturvedula
Jul 22, 2016·CPT: Pharmacometrics & Systems Pharmacology·S DuwalM von Kleist
Jan 31, 2019·PLoS Computational Biology·Sulav DuwalMax von Kleist
Aug 25, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jennifer E SagerNina Isoherranen
Nov 3, 2010·The Journal of Physical Chemistry. B·M Alcolea Palafox, Jéssica Talaya

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