Pharmacologic Considerations for Therapeutic Success with Antiretroviral Agents

Fletcher, Courtney V.

doi:10.1345/aph.19075

Cited by 40 publications

(26 citation statements)

References 31 publications

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“…Individual variation in response, such as viral suppression and adverse effects, to antiretroviral therapy is a well-described phenomenon (19,49). Epidemiological and limited clinical studies suggest that demographic characteristics (e.g., gender, age, and ethnicity) and the HIV disease state of an individual may be partly responsible for the variation in efficacy and toxicity observed with treatment by nucleoside analog reverse transcriptase inhibitors (NRTIs).…”

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confidence: 99%

Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites

Paintsil¹,

Dutschman²,

Hu³

et al. 2011

Antimicrob Agents Chemother

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Individual variation in response to antiretroviral therapy is well-known, but it is not clear if demographic characteristics such as gender, age, and ethnicity are responsible for the variation. To optimize anti-HIV therapy and guide antiretroviral drug discovery, determinants that cause variable responses to therapy need to be evaluated. We investigated the determinants of intracellular concentrations of nucleoside analogs using peripheral blood mononuclear cells from 40 healthy donors. We observed individual differences in the concentrations of the intracellular nucleoside analogs; the mean concentrations of the triphosphate metabolite of ethynylstavudine (4-Ed4T), zidovudine (AZT), and lamivudine (3TC) were 0.71 pmol/10 6 cells (minimum and maximum, 0.10 and 3.00 pmol/10 6 cells, respectively), 0.88 pmol/10 6 cells (minimum and maximum, 0.10 and 15.18 pmol/10 6 cells, respectively), and 1.70 pmol/10 6 cells (minimum and maximum, 0.20 and 7.73 pmol/10 6 cells, respectively). Gender and ethnicity had no effect on the concentration of 4-Ed4T and 3TC metabolites. There was a trend for moderation of the concentrations of AZT metabolites by gender (P ‫؍‬ 0.17 for gender ⅐ metabolite concentration). We observed variability in the activity and expression of cellular kinases. There was no statistically significant correlation between thymidine kinase 1 (TK-1) activity or expression and thymidine analog metabolite concentrations. The correlation between the activity of deoxycytidine kinase (dCK) and the 3TC monophosphate metabolite concentration showed a trend toward significance (P ‫؍‬ 0.1). We observed an inverse correlation between the multidrug-resistant protein 2 (MRP2) expression index and the concentrations of AZT monophosphate, AZT triphosphate, and total AZT metabolites. Our findings suggest that the observed variation in clinical response to nucleoside analogs may be due partly to the individual differences in the intracellular concentrations, which in turn may be affected by the cellular kinases involved in the phosphorylation pathway and ATP-binding cassette (ABC) transport proteins.Individual variation in response, such as viral suppression and adverse effects, to antiretroviral therapy is a well-described phenomenon (19, 49). Epidemiological and limited clinical studies suggest that demographic characteristics (e.g., gender, age, and ethnicity) and the HIV disease state of an individual may be partly responsible for the variation in efficacy and toxicity observed with treatment by nucleoside analog reverse transcriptase inhibitors (NRTIs). For example, published studies show that women experienced a 4-fold lower rate of disease progression than did men while they were on zidovudine (AZT) monotherapy; however, women experienced exaggerated toxicities during NRTI therapy compared to those of men (15-17, 20, 37). Gender and ethnicity have been suggested to be possible variables that explain the observed differences in treatment response to NRTIs (1,16,43).In a cohort of 4 HIV-1-infected women and 29 HIV-1-in...

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confidence: 99%

Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites

Paintsil¹,

Dutschman²,

Hu³

et al. 2011

Antimicrob Agents Chemother

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“…However, the treatment outcome is not always satisfactory (7). This can depend on different virological, immunological, behavioral, or pharmacological factors (5). In the framework of aspects, the interaction between P-glycoprotein (P-gp) and antiretroviral drugs has been evidenced (8,13,15).…”

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P-Glycoprotein Expression by Peripheral Blood Mononuclear Cells from Human Immunodeficiency Virus-Infected Patients Is Independent from Response to Highly Active Antiretroviral Therapy

Agrati

Poccia

Topino

et al. 2003

Clin Vaccine Immunol

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“…Despite these advances, failure of therapeutic regimens to control viral replication is a major concern in the management of patients with HIV infection. Several factors are believed to contribute to this failure, including subtherapeutic drug concentrations resulting from drug interactions (22), adverse events (5), and poor adherence or nonadherence to the prescribed regimen because the regimens are complex and require frequent dosing with a large number of capsules (29).A strong correlation between antiviral activity and the concentrations of PIs in plasma has been demonstrated in several studies (1,7,8,18,26,28). Subtherapeutic concentrations of PIs in plasma can be associated with viral rebound and the development of drug resistance, indicating the importance of maintaining consistent drug concentrations in plasma (1,7,8,18,26,28).…”

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confidence: 99%

“…Subtherapeutic concentrations of PIs in plasma can be associated with viral rebound and the development of drug resistance, indicating the importance of maintaining consistent drug concentrations in plasma (1,7,8,18,26,28). A regimen that results in increased trough exposures could potentially provide therapy for patients with drugresistant viruses and make once-daily (q.d.)…”

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Pharmacokinetic Modeling and Simulations of Interaction of Amprenavir and Ritonavir

Sale

Sadler

Stein

2002

Antimicrob Agents Chemother

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Data from three pharmacokinetic drug interaction studies of amprenavir and ritonavir were used to develop a pharmacokinetic interaction model using NONMEM (nonlinear mixed-effect model). A two-compartment linear model with first-order absorption best fit the amprenavir data, while a one-compartment model was used to describe the ritonavir data. The inhibition of elimination of amprenavir by ritonavir was modeled with a maximum effect (E max ) inhibition model and the observed ritonavir concentration. Monte Carlo simulation was then used to predict amprenavir concentrations for various combinations of amprenavir and ritonavir in twice-daily and once-daily dosing regimens. Simulated minimum amprenavir concentrations in plasma (C min ) in twice-daily and once-daily dosing regimens were compared with protein binding-adjusted 50% inhibitory concentrations (IC 50 s) for clinical human immunodeficiency virus isolates with different susceptibilities to protease inhibitors (central tendency ratios). The model based on the first two studies predicted the results of the third study. Data from all three studies were then combined to refine the final model. The observed and simulated noncompartmental pharmacokinetic parameters agreed well. From this model, several candidate drug regimens were simulated. These simulations suggest that, in patients who have clinically failed a traditional amprenavir regimen, a regimen of 600 mg of amprenavir with 100 mg of ritonavir twice daily would result in C min -to-IC 50 ratios similar to that of 1,200 mg of amprenavir twice daily alone for wild-type viruses. In addition, once-daily regimens that result in C min s above the protein binding-corrected IC 50 s for wild-type virus are clearly feasible.Human immunodeficiency virus (HIV) protease inhibitors (PIs) in combination with reverse transcriptase inhibitors have prolonged and improved the quality of life for HIV-infected patients (2,9,10,17,21). Despite these advances, failure of therapeutic regimens to control viral replication is a major concern in the management of patients with HIV infection. Several factors are believed to contribute to this failure, including subtherapeutic drug concentrations resulting from drug interactions (22), adverse events (5), and poor adherence or nonadherence to the prescribed regimen because the regimens are complex and require frequent dosing with a large number of capsules (29).A strong correlation between antiviral activity and the concentrations of PIs in plasma has been demonstrated in several studies (1,7,8,18,26,28). Subtherapeutic concentrations of PIs in plasma can be associated with viral rebound and the development of drug resistance, indicating the importance of maintaining consistent drug concentrations in plasma (1,7,8,18,26,28). A regimen that results in increased trough exposures could potentially provide therapy for patients with drugresistant viruses and make once-daily (q.d.) dosing a feasible therapeutic option.Amprenavir (Agenerase; formerly 141W94) is a recently introduced HIV PI. ...

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Pharmacologic Considerations for Therapeutic Success with Antiretroviral Agents

Cited by 40 publications

References 31 publications

Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites

Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites

P-Glycoprotein Expression by Peripheral Blood Mononuclear Cells from Human Immunodeficiency Virus-Infected Patients Is Independent from Response to Highly Active Antiretroviral Therapy

Pharmacokinetic Modeling and Simulations of Interaction of Amprenavir and Ritonavir

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