Concentration-controlled zidovudine therapy*

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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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

“…In the field of human immunodeficiency virus (HIV) therapeutics, substantial interpatient pharmacokinetic variability has been demonstrated and relationships between drug exposure and viral response have been observed for all three classes of antiretroviral agents (2, 6). Importantly, dose adjustment strategies designed to achieve target drug exposures and thereby reduce pharmacokinetic variability have resulted in improved virologic and immunologic outcomes (7,8).In addition to pharmacokinetics, another source of variability in outcomes is adherence. Therapeutic drug monitoring and pharmacokinetics have been discussed as approaches to monitor adherence but have not been systematically studied, partly because adherence has not been conceptually integrated into the basic pharmacologic dose-response paradigm.…”

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confidence: 99%

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confidence: 99%

Intrapatient Variability of Efavirenz Concentrations as a Predictor of Virologic Response to Antiretroviral Therapy

Brundage

Yong

Fenton

et al. 2004

Self Cite

Intrapatient variability of drug concentrations over time has not been evaluated as a predictor of drug response but may provide information on the onset and maintenance of response and a patient's adherence to therapy. Our objective was to develop a pharmacologically based measure of intrapatient variability of concentrations and investigate its association with a patient's response to antiretroviral therapy. Efavirenz concentrations were obtained for 50 children enrolled in Pediatric AIDS Clinical Trials Group study 382, a concentration-controlled trial of efavirenz plus nelfinavir and at least one nucleoside reverse transcriptase inhibitor. Efavirenz pharmacokinetic parameters were determined from 24-h concentration-time profiles at weeks 2 and 6 and used to predict trough concentrations obtained during 1 year of therapy. A concentration predictability score, defined as the fraction of measured trough concentrations that fell within a ؎50% range of the predicted concentration, was used to place subjects into high and low concentration predictability groups. Relationships between this score and human immunodeficiency virus RNA levels in plasma were investigated. Eight of 33 children (24%) in the high-predictability group experienced viral rebound, compared with 9 of 17 children (53%) in the low-predictability group (P ‫؍‬ 0.042). Children with low predictability scores exhibited a significantly shorter time to their first viral rebounds and were significantly more likely to experience viral rebound; the latter finding persisted after adjustment for baseline viral load and efavirenz exposure at week 6. This novel method for the quantitation of intrapatient concentration variability was independently predictive of virologic rebound. This measure may allow interventions to minimize therapeutic failure and is applicable to other drugs.Variability in response to antiretroviral therapy has been attributed to differences in virologic, immunologic, pharmacologic, and behavioral characteristics. In the field of human immunodeficiency virus (HIV) therapeutics, substantial interpatient pharmacokinetic variability has been demonstrated and relationships between drug exposure and viral response have been observed for all three classes of antiretroviral agents (2, 6). Importantly, dose adjustment strategies designed to achieve target drug exposures and thereby reduce pharmacokinetic variability have resulted in improved virologic and immunologic outcomes (7,8).In addition to pharmacokinetics, another source of variability in outcomes is adherence. Therapeutic drug monitoring and pharmacokinetics have been discussed as approaches to monitor adherence but have not been systematically studied, partly because adherence has not been conceptually integrated into the basic pharmacologic dose-response paradigm. In the standard model, pharmacokinetics describes the relationship between dose and concentration and pharmacodynamics describes the relationship between concentration and response. While this paradigm has proven quite usefu...

“…Studies conducted with HIV-infected populations have not established any relationship between ZDV or 3TC concentrations in plasma and the efficacy of these agents (19). On the other hand, a recent study showed a linear relationship between ZDV-TP intracellular concentrations and an increase in the percent change in CD4 ϩ cells from baseline in HIV-infected adults (5 Several approaches have been reported for the individual determination of ZDV-TP and 3TC-TP (6, 13, 15-18, 21, 22, 24). A recent approach was developed in which strong anionexchange-solid-phase extraction separated ZDV anabolites (ZDV-MP, ZDV-DP, and ZDV-TP), followed by enzyme digestion and quantification by radioimmunoassay (18).…”

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confidence: 99%

Simultaneous Quantitation of Intracellular Zidovudine and Lamivudine Triphosphates in Human Immunodeficiency Virus-Infected Individuals

Rodrı́guez

Rodriguez²,

Santana

et al. 2000

Highly active antiretroviral therapy (HAART) is the standard treatment for infection with human immunodeficiency virus (HIV).The most common HAART regimen consists of the combination of at least one protease inhibitor (PI) with two nucleoside reverse transcriptase inhibitors (NRTIs). Contrary to PIs, NRTIs require intracellular activation from the parent compound of their triphosphate moiety to suppress HIV replication. Simultaneous intracellular determination of two NRTI triphosphates is difficult to accomplish due to their relatively small concentrations in peripheral blood mononuclear cells (PBMCs), requiring large amounts of blood from HIV-positive patients. Recently, we described a method to determine intracellular zidovudine triphosphate (ZDV-TP) concentrations in HIV-infected patients by using solid-phase extraction and tandem mass spectrometry. The limit of quantitation (LOQ) for ZDV-TP was 0.10 pmol, and the method was successfully used for the determination of ZDV-TP in HIV-positive patients. In this study, we enhanced the aforementioned method by the simultaneous quantitation of ZDV-TP and lamivudine triphosphate (3TC-TP) in PBMCs from HIV-infected patients. The LOQ for 3TC-TP was 4.0 pmol, with an interassay coefficient of variation and an accuracy of 7 and 12%, respectively. This method was successfully applied to the simultaneous in vivo determination of the ZDV-TP and 3TC-TP pharmacokinetic profiles from HIV-infected patients receiving HAART.Highly active antiretroviral therapy (HAART) has been used successfully for treatment of human immunodeficiency virus (HIV) since the discovery of protease inhibitors (PIs) (3,4,20). HAART treatment includes a broad category of antiretroviral drug combinations with the goals of decreasing plasma HIV-1 RNA levels below the limit of detection, limiting disease progression, and delaying the appearance of resistant mutants (12). The most common HAART regimen consists of the combination of one PI with two nucleoside reverse transcriptase inhibitors (NRTIs). This triple drug combination has shown dramatic improvements in viral suppression over the combination of the two nucleosides zidovudine and lamivudine (ZDV and 3TC, respectively) (8-10).Contrary to PIs, NRTIs require intracellular activation from the parent compound of their triphosphate (TP) moiety to suppress HIV replication. ZDV and 3TC are not active against HIV; they need to be metabolized to 5Ј-ZDV-TP (ZDV-TP) and 5Ј-3TC-TP (3TC-TP) to act as competitive inhibitors of HIV reverse transcriptase or be incorporated into the viral genome (2,7,11,23). Studies conducted with HIV-infected populations have not established any relationship between ZDV or 3TC concentrations in plasma and the efficacy of these agents (19). On the other hand, a recent study showed a linear relationship between ZDV-TP intracellular concentrations and an increase in the percent change in CD4 ϩ cells from baseline in HIV-infected adults (5). Furthermore, several stud- Several approaches have been reported for the individual determinatio...