Pharmacokinetic variability of zidovudine in HIV-infected individuals

Burger, D.M.; Pl, Meenhorst; Napel, ten; Jw, Mulder; Neef, Cees; Ch, Koks; Bult, A.; Jh, Beijnen

doi:10.1097/00002030-199412000-00007

Cited by 42 publications

(21 citation statements)

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“…(16). Although the oral clearance of ZDV may be reduced in individuals with body weights Ͻ60 kg (10,90), other studies have failed to demonstrate a linear relationship between body weight and ZDV clearance (78). Furthermore, the wide interindividual variance in cellular TK 1 and TMPK (45,48) suggests that plasma concentrations of ZDV alone would be insufficient to predict levels of the active ZDV-TP.…”

Section: Discussionmentioning

confidence: 99%

“…Like other NRTI, ZDV undergoes three intracellular phosphorylation steps to form the active ZDV-5Ј-triphosphate (ZDV-TP), which inhibits wild-type HIV-1 RT with a median inhibitory concentration of about 0.035 M (72). The single-dose plasma pharmacokinetics of ZDV have been well described in HIV-1-infected individuals following intravenous and oral administration (1,10,20,34,65,78,90).…”

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confidence: 99%

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Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model

Hurwitz

Asif

Kivel³

et al. 2008

Antimicrob Agents Chemother

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In vitro selection studies and data from large genotype databases from clinical studies have demonstrated that tenofovir disoproxil fumarate and abacavir sulfate select for the K65R mutation in the human immunodeficiency virus type 1 polymerase region. Furthermore, other novel non-thymine nucleoside reverse transcriptase (RT) inhibitors also select for this mutation in vitro. Studies performed in vitro and in humans suggest that viruses containing the K65R mutation remained susceptible to zidovudine (ZDV) and other thymine nucleoside antiretroviral agents. Therefore, ZDV could be coformulated with these agents as a "resistance repellent" agent for the K65R mutation. The approved ZDV oral dose is 300 mg twice a day (b.i.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model

Hurwitz

Asif

Kivel³

et al. 2008

Antimicrob Agents Chemother

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“…Moreover, there are no published studies concerning gender-related differences in tissue distribution of nucleoside transporters, although gender differences in the disposition and toxicity of nucleoside analogs have been reported in humans (Burger et al, 1994;Pai and Nahata, 2000;Ofotokun and Pomeroy, 2003). In drug development, pharmacokinetics/toxicology (and frequently efficacy) studies in rats and mice are required before conducting clinical studies in humans.…”

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confidence: 99%

Tissue Distribution of Concentrative and Equilibrative Nucleoside Transporters in Male and Female Rats and Mice

Chen²,

2004

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ABSTRACT:Concentrative nucleoside transporters (Cnts) and equilibrative nucleoside transporters (Ents) have essential physiological functions and are important in disposition of anticancer and antiviral nucleoside analogs. Information on tissue distribution of Cnts and Ents in rodents is sparse. Thus, the present study aimed to determine the distribution of Cnt1-3 and Ent1-3 transcripts in 19 tissues of Sprague-Dawley rats and C57BL/6 mice of both genders. These six transcripts were quantified using the branched DNA signal amplification assay. Cnt1 transcripts were highest in small intestine, followed by kidney and testes, with similar expression in both species. Cnt2 mRNA was expressed highest in the small intestine of both rats and mice, intermediate in liver of rats but not in mice, and lower in thymus and spleen of both species. Cnt3 mRNA has marked species differences, with the highest expression in lung of rats but uterus of mice. Ent1 mRNA was most highly expressed in testes and lung of both species. Ent1 mRNA was highly expressed in liver and pituitary of mice, but not in rats. Ent2 mRNA was highly expressed in testes and brain of both species. Ent3 mRNA was highest in kidney, followed by testes, in both species. Significant gender differences were observed in kidney (mouse) and heart (rat). These studies demonstrate that in general, tissue distribution of Cnt and Ent is similar in rats and mice. However, a few important species and gender differences do exist, which could be responsible for related differences in efficacy and toxicity of substrates for these transporters.

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“…There was general improvement in precision and bias between these two methods with the use of V/F, and therefore CL/F, as a weight-adjusted parameter, although this was not statistically significant. There are conflicting data in the literature as to whether weight is an important variable in V/F and CL/F of zidovudine (3,15,21,24,30). All of these investigations administered oral zidovudine, and therefore F was not independently identified.…”

Section: Discussionmentioning

confidence: 99%

“…Participants were persons with laboratorydocumented HIV infection, aged 18 to 60 years, currently stabilized on at least 300 mg of zidovudine per day, and with Karnofsky performance status of at least 60% and stable bone marrow, renal, and hepatic function. Exclusion or termination criteria were presence of an active opportunistic infection requiring therapy, three or more liquid stools per day, nausea or vomiting, zidovudine-associated anemia (hemoglobin level of less than 7 g/dl) or neutropenia (absolute neutrophil count less than 1,000 cells per mm 3 ), or noncompliance with prescribed medications or scheduled clinic visits. Participants in this study continued to take zidovudine and any other concomitant medications prescribed by their physician; no alterations in these drugs or dosing regimens were made as part of participation in this study.…”

Section: Methodsmentioning

confidence: 99%

Strategies for control of zidovudine concentrations in serum

Noormohamed

Henry

Rhame

et al. 1995

Antimicrob Agents Chemother

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There are several clinical scenarios in which knowledge of zidovudine disposition may be important. This study evaluated the clinical utility of pharmacokinetic parameters for zidovudine derived from sparse serum concentration data obtained in an outpatient setting. Twelve human immunodeficiency virus-infected participants had two serum zidovudine concentration determinations obtained on two different clinic visits, 2 to 38 days apart. Zidovudine concentrations were measured by radioimmunoassay. A one-compartment oral absorption model was used to describe zidovudine disposition. Three different approaches were used to estimate pharmacokinetic parameters: Bayesian estimation with one or two concentrations and least squares with one concentration. The ability of these parameters to predict concentrations measured during the second clinic visit was assessed by calculation of precision and bias and compared with predictions using standard fixed or weight-adjusted parameters. Estimated pharmacokinetic parameters for zidovudine were consistent with literature values; there was no statistically significant difference among the parameters calculated with the three estimation strategies. Absorptive phase concentrations were poorly predicted by all methods (mean percent bias, 157 to 249%; mean percent precision, 389 to 537%). Predictive ability for concentrations obtained in the elimination phase was strikingly improved: mean percent bias, ؊17 to 70%; mean percent precision, 40 to 95%. Bayesian and least-squares estimated parameters were statistically better than fixed-parameter values for predicting concentrations in the elimination phase. These observations provide a modeling framework to determine pharmacokinetic disposition of zidovudine in an individual, screen for the existence of a drug interaction, and conduct concentration-controlled clinical trials.

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Pharmacokinetic variability of zidovudine in HIV-infected individuals

Cited by 42 publications

References 0 publications

Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model

Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model

Tissue Distribution of Concentrative and Equilibrative Nucleoside Transporters in Male and Female Rats and Mice

Strategies for control of zidovudine concentrations in serum

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