The effect of zidovudine dose on the formation of intracellular phosphorylated metabolites

Barry, Michael; Khoo, Saye; Veal, Gareth J.; Hoggard, Patrick G.; Gibbons, Sara; Wilkins, E.G.L.; Williams, Olwen; Breckenridge, Alasdair; Back, David

doi:10.1097/00002030-199610000-00008

Cited by 83 publications

(59 citation statements)

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“…The majority of model parameters were available from in vitro or in vivo experiments (see Table 3); the remaining three parameters were estimated from the in vivo data (see Table 2). The model was evaluated against experimental in vivo data of different dosing schemes (Barry et al (1996): 100mg; Aweeka et al (2007); Barry et al (1996): 300mg;Flynn et al (2007): 600mg) in HIV infected patients. While most studies only measure plasma levels of the pro-drug zidovudine, intra-cellular PBMC levels of the active zidovudine anabolites are rarely available.…”

Section: Discussionmentioning

confidence: 99%

“…It has been observed that the cellular amounts of zidovudine diphosphate (AZT-DP) and AZT-TP are significantly smaller than the corresponding AZT and AZT-MP levels (approximately 1:100) (Wattanagoon et al, 2000;Barry et al, 1996;Rodman et al, 1996;Aweeka et al, 2007;Toyoshima et al, 1991;Furman et al, 1986;Arnér et al, 1992;Flynn et al, 2007). The levels of di-and triphosphates in the rest of the body insignificantly influence the kinetics of AZT and AZT-MP (Chow et al, 1997).…”

Section: Detailed Physiologically Based Pharmacokinetic Model Of Zidomentioning

confidence: 99%

“…The total number of PBMCs is the sum of the CD4 + and CD4 − cells. The former are available for the different studies (Barry et al, 1996;Aweeka et al, 2007;Flynn et al, 2007;Marier et al, 2007), while the latter has been set to 800 [10 6 cells/L] (based on an average total PBMC count of 1600 in healthy subjects, with a CD4 − fraction of ∼ 50%) (Bisset et al, 2004).…”

Section: Detailed Physiologically Based Pharmacokinetic Model Of Zidomentioning

confidence: 99%

“…(Panhard et al, 2007;Capparelli et al, 2003)). However, the relation between AZT and AZT-TP was shown to be non-linear (Wattanagoon et al, 2000;Stretcher et al, 1991;Anderson et al, 2003;Barry et al, 1996;Rodman et al, 1996;Aweeka et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

Kleist¹,

Huisinga²

2009

European Journal of Pharmaceutical Sciences

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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 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 threecompartment 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 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 insufficient viral suppression was observed for almost half the dosing period.

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Section: Discussionmentioning

confidence: 99%

Section: Detailed Physiologically Based Pharmacokinetic Model Of Zidomentioning

confidence: 99%

Section: Detailed Physiologically Based Pharmacokinetic Model Of Zidomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Kleist¹,

Huisinga²

2009

European Journal of Pharmaceutical Sciences

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“…61,[69][70][71] The half-life of ZDV-TP is about 7 hours and that for 3TC-TP is about 22 hours. 69 These half-lives for the pharmacologically active moieties are several-fold longer than the parent drug in plasma, and form the pharmacokinetic rationale for the dosing frequencies used in patients today (twice daily for ZDV and once-or twice-daily for 3TC).…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

Zidovudine and Lamivudine for HIV Infection

Anderson

Rower²

2010

Clinical Medicine Reviews in Therapeutics

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Zidovudine and lamivudine (ZDV and 3TC) are long-standing nucleoside analog-reverse transcriptase inhibitors (NRTIs) with extensive clinical experience in a wide spectrum of patients from in utero through childhood and adult ages. The safety profiles of both drugs are well-known and side effects for ZDV most commonly include nausea/vomiting, fatigue, anemia/neutopenia, and lipoatrophy; while 3TC is well-tolerated. ZDV-3TC is currently a viable alternative NRTI backbone for initial three-drug therapy of HIV infection when tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) cannot be used because of a relative or absolute contraindication. ZDV-3TC continue to be viable alternatives for children, pregnant women and in resource limited settings where other recommended options are not readily available. ZDV-3TC penetrate the Central Nervous System (CNS) well, which makes ZDV-3TC attractive for use in patients with HIV-associated neurological deficits. Additional benefits of these drugs may include the use of ZDV in combination with certain NRTIs to exert selective pressure to prevent particular drug resistance mutations from developing, and giving a short course of ZDV-3TC to prevent resistance after prophylactic single dose nevirapine.

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Concurrent analysis of nucleoside reverse transcriptase inhibitors in a pool of endogenous nucleosides by short-end injection-capillary electrochromatography on a β-cyclodextrin-bonded stationary phase

2002

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As part of our on-going study of the analysis of anti-human immunodeficiency virus (HIV) nucleosides, a capillary electrochromatography (CEC) method has been developed for the concurrent analysis of nucleoside HIV reverse transcriptase inhibitors (NRTIs) in a pool of endogenous nucleosides. Up to now, beta-cyclodextrin-bonded silica stationary phases have mainly been dedicated to the separation of enantiomers; however, these polysaccharides can be also be used in achiral way. This work aims at showing how CEC performed on a beta-cyclodextrin-bonded silica stationary phase can be used to concurrently resolve zidovudine (AZT), lamivudine (3TC), didanosine (ddA) and its administrated form (ddI), stavudine (d4T) and hivid (ddC) in a mixture of adenosine (A), cytidine (C), guanosine (G), thymidine (T) and uridine (U). The influence of several parameters (pH buffer, ionic strength, acetonitrile content, temperature and voltage) on both the retention times and the retention factors has been investigated using the short-end injection technique to achieve baseline separation in a short-time analysis before quantitation. Moreover, the retention factors of the charged solutes in short-end injection-CEC were calculated using theoretically derived equations, allowing for the actual voltage drop in the packed section of the semipacked CEC capillary.

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The effect of zidovudine dose on the formation of intracellular phosphorylated metabolites

Cited by 83 publications

References 0 publications

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

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

Zidovudine and Lamivudine for HIV Infection

Concurrent analysis of nucleoside reverse transcriptase inhibitors in a pool of endogenous nucleosides by short-end injection-capillary electrochromatography on a β-cyclodextrin-bonded stationary phase

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