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Joseph J. Eron - One of the best experts on this subject based on the ideXlab platform.
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a 42 week open label study to assess the pharmacokinetics antiretroviral activity and safety of Amprenavir or Amprenavir plus ritonavir in combination with abacavir and lamivudine for treatment of hiv infected patients
Clinical Infectious Diseases, 2004Co-Authors: Robin Wood, Keikawus Arastéh, Eugenio Teofilo, Joseph J. Eron, Judith Millard, Mary Beth Wire, Christian Trepo, Jean Michel Livrozet, Odin J. NadererAbstract:The pharmacokinetics, antiviral activity, and safety of an Amprenavir-ritonavir (APV-RTV) 600/100 mg b.i.d. regimen and an APV-RTV 1200/200 mg q.d. regimen were studied in a human immunodeficiency virus (HIV)-infected population. The geometric least-square mean ratio (90% confidence interval) of steady-state trough concentrations, compared with that of the Amprenavir 1200 mg b.i.d. regimen, was 6.08 (4.94-7.49) for the twice-daily APV-RTV regimen, and it was 4.19 (2.90-6.08) for the daily APV-RTV regimen. The regimens were well tolerated, which supports APV-RTV as an option for twice-daily or daily therapy for HIV.
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The Pharmacokinetics, Safety, and Initial Virologic Response of a Triple–protease Inhibitor Salvage Regimen Containing Amprenavir, Saquinavir, and Ritonavir
Journal of acquired immune deficiency syndromes (1999), 2004Co-Authors: Amanda H. Corbett, Joseph J. Eron, Susan A. Fiscus, Naser L. Rezk, Angela D. M. KashubaAbstract:The aim of this study was to quantify the change in saquinavir and Amprenavir exposure when combined and used with low-dose ritonavir; to evaluate 24-week safety and immunologic and virologic response. It was a randomized, nonblinded, prospective study. There were 11 HIV-1-infected, antiretroviral-experienced, male and female subjects > or = 18 years old, median HIV-1 RNA and CD4(+) T-cell count of 4.86 log copies/mL and 10(6) cells/mm(3), respectively. Subjects were randomly assigned to receive saquinavir 1000 mg/ritonavir 100 mg every 12 hours or Amprenavir 600 mg/ritonavir 100 mg every 12 hours for 7 days. After 12-hour pharmacokinetic sampling, the third protease inhibitor (PI) was added, and pharmacokinetics sampling was repeated 14 days later. Subsequent PI dosage adjustments were based on real-time pharmacokinetic assessment. Saquinavir did not affect Amprenavir or ritonavir pharmacokinetics. Amprenavir decreased area under the concentration-time curve (AUC(0-12h)) and C(12h) for saquinavir 82 and 61%, and 74 and 75% for ritonavir. An adjusted PI regimen of Amprenavir 600 mg/saquinavir 1400 mg/ritonavir 200 mg every 12 hours returned saquinavir exposure to baseline. At 24 weeks, HIV RNA declined a median of 1.55 log copies/mL and CD4(+) T-cell counts increased a median of 52 cells/mm(3). Gastrointestinal events predominated and were mild to moderate. These data suggest that Amprenavir/saquinavir/ritonavir may be a viable salvage regimen in heavily PI-experienced individuals. New formulations of Amprenavir and saquinavir may simplify this regimen.
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the pharmacokinetics safety and initial virologic response of a triple protease inhibitor salvage regimen containing Amprenavir saquinavir and ritonavir
Journal of Acquired Immune Deficiency Syndromes, 2004Co-Authors: Amanda H. Corbett, Joseph J. Eron, Susan A. Fiscus, Naser L. Rezk, Angela D. M. KashubaAbstract:The aim of this study was to quantify the change in saquinavir and Amprenavir exposure when combined and used with low-dose ritonavir; to evaluate 24-week safety and immunologic and virologic response. It was a randomized, nonblinded, prospective study. There were 11 HIV-1-infected, antiretroviral-experienced, male and female subjects > or = 18 years old, median HIV-1 RNA and CD4(+) T-cell count of 4.86 log copies/mL and 10(6) cells/mm(3), respectively. Subjects were randomly assigned to receive saquinavir 1000 mg/ritonavir 100 mg every 12 hours or Amprenavir 600 mg/ritonavir 100 mg every 12 hours for 7 days. After 12-hour pharmacokinetic sampling, the third protease inhibitor (PI) was added, and pharmacokinetics sampling was repeated 14 days later. Subsequent PI dosage adjustments were based on real-time pharmacokinetic assessment. Saquinavir did not affect Amprenavir or ritonavir pharmacokinetics. Amprenavir decreased area under the concentration-time curve (AUC(0-12h)) and C(12h) for saquinavir 82 and 61%, and 74 and 75% for ritonavir. An adjusted PI regimen of Amprenavir 600 mg/saquinavir 1400 mg/ritonavir 200 mg every 12 hours returned saquinavir exposure to baseline. At 24 weeks, HIV RNA declined a median of 1.55 log copies/mL and CD4(+) T-cell counts increased a median of 52 cells/mm(3). Gastrointestinal events predominated and were mild to moderate. These data suggest that Amprenavir/saquinavir/ritonavir may be a viable salvage regimen in heavily PI-experienced individuals. New formulations of Amprenavir and saquinavir may simplify this regimen.
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Six-Week Randomized Controlled Trial To Compare the Tolerabilities, Pharmacokinetics, and Antiviral Activities of GW433908 and Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients
Antimicrobial agents and chemotherapy, 2004Co-Authors: Robin Wood, Keikawus Arastéh, Hans Jürgen Stellbrink, Eugenio Teofilo, François Raffi, Richard B. Pollard, Joseph J. Eron, Jane Yeo, Judith Millard, Mary Beth WireAbstract:This study compared the plasma Amprenavir pharmacokinetics of the human immunodeficiency virus (HIV) protease inhibitors Amprenavir (Agenerase) 1,200 mg twice daily (BID) and the Amprenavir prodrug GW433908, a formulation that substantially reduces the number of tablets per dose compared with Amprenavir, at doses of 1,395 mg and 1,860 mg BID, in combination with abacavir 300 mg BID and lamivudine 150 mg BID in patients with HIV infection. Overall, 78 patients received study treatment. Compared with Amprenavir 1,200 mg BID, both GW433908 1,395 mg BID and GW433908 1,860 mg BID delivered equivalent steady-state (ss) values for area under the plasma Amprenavir concentration-time curve (AUC) at the end of a dosing interval (τ), lower maximum plasma Amprenavir concentrations (30% lower), and higher plasma Amprenavir concentrations at the end of a dosing interval (28% higher for GW433908 1,395 mg BID and 46% higher for GW433908 1,860 mg BID). Time-variant plasma Amprenavir pharmacokinetics were observed with reductions in plasma Amprenavir exposure over the first 4 weeks of dosing; the decrease in plasma Amprenavir AUC τ,ss versus the AUC from 0 h to ∞ was 27% for GW43308 1,395 mg, 45% for GW433908 1,860 mg, and 23% for Amprenavir 1,200 mg. All three regimens reduced plasma HIV-1 RNA (∼2 log 10 copies/ml) and increased CD4 + cell counts (∼100 cells/mm 3 ) over the initial 28 days. Adverse event profiles were consistent with those previously reported for Amprenavir. Although not statistically tested, the GW433908 groups appeared to have fewer gastrointestinal symptoms. In conclusion, the protease inhibitor GW433908 delivered comparable plasma Amprenavir concentrations to those delivered by Amprenavir 1,200 mg BID. GW433908, in combination with abacavir and lamivudine, demonstrated potent antiviral activity and was generally well tolerated over a 4-week period.
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Effects of formulation and dosing strategy on Amprenavir concentrations in the seminal plasma of human immunodeficiency virus type 1-infected men.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2002Co-Authors: Naumann I. Chaudry, Joseph J. Eron, Mary Beth Wire, Odin J. Naderer, Arlene S. Pereira, Susan A. Fiscus, Angela D. M. KashubaAbstract:We compared seminal plasma pharmacokinetic data for the investigational Amprenavir prodrug GW433908 with those for Amprenavir and an Amprenavir-ritonavir combination regimen. All 3 regimens resulted in detectable blood plasma and seminal plasma concentrations of Amprenavir. The majority of these concentrations were greater than the plasma protein--corrected 50% inhibitory concentration for wild-type human immunodeficiency virus type 1.
Brian M. Sadler - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic Modeling and Simulations of Interaction of Amprenavir and Ritonavir
Antimicrobial agents and chemotherapy, 2002Co-Authors: Mark Sale, Brian M. Sadler, Daniel S. SteinAbstract: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 (Emax) 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 (Cmin) in twice-daily and once-daily dosing regimens were compared with protein binding-adjusted 50% inhibitory concentrations (IC50s) 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 Cmin-to-IC50 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 IC50s for wild-type virus are clearly feasible.
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Pharmacokinetic Study of Human Immunodeficiency Virus Protease Inhibitors Used in Combination with Amprenavir
Antimicrobial agents and chemotherapy, 2001Co-Authors: Brian M. Sadler, Catherine Gillotin, Joseph J. Eron, Yu Lou, Richard Haubrich, William Lang, Daniel S. SteinAbstract:In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of Amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that Amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUC ss ] and 37% for peak plasma concentration at steady state [ C max,ss ]) and increased by indinavir (33% for AUC ss ). Nelfinavir significantly increased Amprenavir minimum drug concentration at steady state (by 189%) but did not affect Amprenavir AUC ss or C max,ss . Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with Amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with Amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in Amprenavir steady-state pharmacokinetic parameters, relative to those for Amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.
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In Vivo Effect of α1-Acid Glycoprotein on Pharmacokinetics of Amprenavir, a Human Immunodeficiency Virus Protease Inhibitor
Antimicrobial agents and chemotherapy, 2001Co-Authors: Brian M. Sadler, Catherine Gillotin, Yu Lou, Daniel S. SteinAbstract:Observations from early clinical pharmacology studies of Amprenavir, an inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that is highly bound to human plasma proteins (∼90%), showed the single-dose pharmacokinetics of Amprenavir to be variable between and within individuals. A cross-study analysis of various demographic, laboratory, and clinical covariates was therefore performed. Differences in Amprenavir pharmacokinetics could be due to variable concentrations in α 1 -acid glycoprotein (AAG), the predominant plasma protein to which Amprenavir binds. Therefore, AAG was considered an important factor to study since the literature suggested that AAG levels vary by race, age, and weight and following trauma or infection, including HIV disease. Pooled data from three single-dose studies analyzed by stepwise linear regression indicated that AAG concentrations significantly correlated with age and race and that only AAG concentrations were a significant predictor of Amprenavir apparent total clearance (CL/F). A significant inverse linear relationship was found between AAG and Amprenavir CL/F. Compared to white subjects, black subjects had significantly lower AAG concentrations and therefore significantly higher Amprenavir CL/F. Although AAG has a significant influence on the variability of total drug pharmacokinetics, unbound, or free, drug concentrations are not affected by AAG concentrations. Incorrect conclusions could be drawn on the pharmacokinetics of highly protein-bound drugs if AAG concentration is not included in the analysis.
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Pharmacokinetic Interaction between Amprenavir and Rifabutin or Rifampin in Healthy Males
Antimicrobial agents and chemotherapy, 2001Co-Authors: Ronald E. Polk, Brian M. Sadler, Donald F. Brophy, D S Israel, Roberto L. Patron, Gregory E. Chittick, William T. Symonds, Yu Lou, Debbie Kristoff, Daniel S. SteinAbstract:The objective of this study was to determine if there is a pharmacokinetic interaction when Amprenavir is given with rifabutin or rifampin and to determine the effects of these drugs on the erythromycin breath test (ERMBT). Twenty-four healthy male subjects were randomized to one of two cohorts. All subjects received Amprenavir (1,200 mg twice a day) for 4 days, followed by a 7-day washout period, followed by either rifabutin (300 mg once a day [QD]) (cohort 1) or rifampin (600 mg QD) (cohort 2) for 14 days. Cohort 1 then received Amprenavir plus rifabutin for 10 days, and cohort 2 received Amprenavir plus rifampin for 4 days. Serial plasma and urine samples for measurement of Amprenavir, rifabutin, and rifampin and their 25-O-desacetyl metabolites, were measured by high-performance liquid chromatography. Rifabutin did not significantly affect Amprenavir's pharmacokinetics. Amprenavir significantly increased the area under the curve at steady state (AUCss) of rifabutin by 2.93-fold and the AUCss of 25-O-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUCss of Amprenavir by 82%, but Amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decreased the results of the ERMBT by 83%. The results of the ERMBT after 2 weeks of rifabutin and rifampin therapy were increased 187 and 156%, respectively. Amprenavir plus rifampin was well tolerated. Amprenavir plus rifabutin was poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin markedly increases the metabolic clearance of Amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabutin and 25-O-desacetylrifabutin, and the combination is poorly tolerated. Amprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent inducers of the ERMBT.
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Metabolic Disposition and Pharmacokinetics of [14C]‐Amprenavir, a Human Immunodeficiency Virus Type 1 (HIV‐1) Protease Inhibitor, Administered As a Single Oral Dose to Healthy Male Subjects
Journal of clinical pharmacology, 2001Co-Authors: Brian M. Sadler, Joseph L Woolley, Ronald E. Polk, Gregory E. Chittick, Yu Lou, Scott D. Studenberg, Douglas Slain, Thomas M. Kerkering, Katy H. P. Moore, Daniel S. SteinAbstract:The objective of this study was to determine the metabolic profile, routes of elimination, and total recovery of Amprenavir and its metabolites after a single oral dose of [14C]-Amprenavir. Six healthy male subjects each received a single oral 630 mg dose of Amprenavir containing 95.76 microCi of [14C]-Amprenavir in this Phase I mass balance study. The metabolic disposition of Amprenavir was determined through analyses of radiocarbon in whole blood, plasma, urine, and stool samples, collected for a period of 10 to 17 days postdosing. Cerebral spinal fluid (CSF) sampling was conducted on day 1. The ratio of unchanged Amprenavir AUC0-->infinity to plasma radiocarbon was 27%, suggesting that most of the radiocarbon was metabolites. The median total recovery of the administered dose of radiocarbon was 89% (range: 66%-93%), with 75% (range: 56%-80%) recovered in the feces and 14% (range: 10%-17%) in the urine. Most of the recovered radiocarbon in the feces and urine was excreted within 240 and 48 hours postdose, respectively. Of the 75% of the radiocarbon dose recovered in the feces, 62% was identified as a metabolite resulting from dioxidation of the tetrahydrofuran ring (GW549445X) and 32% as a metabolite resulting from subsequent oxidation of the p-aniline sulfonate group (GW549444X). Unchanged Amprenavir was below the limit of quantitation in feces and urine. Therefore, approximately 94% of the dose excreted in the feces was accounted for by these two metabolites. Concentrations of radiocarbon in the CSF were below the limit of quantitation in 5 of 6 subjects sampled. In summary, oral Amprenavir is extensively metabolized in humans, with concentrations of unchanged drug below the limits of quantitation in urine and feces. The majority (75%) of administered radiocarbon was excreted in feces.
Yu Lou - One of the best experts on this subject based on the ideXlab platform.
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Ritonavir Increases Plasma Amprenavir (APV) Exposure to a Similar Extent when Coadministered with either FosAmprenavir or APV
Antimicrobial agents and chemotherapy, 2006Co-Authors: Mary Beth Wire, Mark J. Shelton, Yu Lou, Katherine L. Baker, Lori S. Jones, Greg J. Thomas, M.m. BerreyAbstract:To compare the effect of ritonavir on plasma Amprenavir pharmacokinetics, healthy adults received either fosAmprenavir (700 mg twice a day [BID]) or Amprenavir (600 mg BID) alone and in combination with ritonavir (100 mg BID). Ritonavir increased plasma Amprenavir pharmacokinetic parameters to a similar extent when coadministered with either fosAmprenavir or Amprenavir.
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Single-Dose Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus Type 1 (HIV-1) Protease Inhibitor, in HIV-Infected Children
Antimicrobial agents and chemotherapy, 2005Co-Authors: Ram Yogev, Yu Lou, Andrea Kovacs, Ellen G. Chadwick, James Homans, William T. SymondsAbstract:A phase I, open-label, dose-escalating trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of single, oral doses of Amprenavir (141W94), a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, in 20 HIV-infected children 4 to 12 years of age. The doses of Amprenavir evaluated, 5, 10, 15, and 20 mg/kg of body weight, were comparable to those evaluated in adult phase I and II studies. The most common clinical adverse event associated with Amprenavir, administered as soft gelatin capsules, was nausea. Amprenavir was rapidly absorbed, with a mean time to maximum concentration ( T max ) occurring 0.95 to 1.58 h after dosing. The area under the concentration-time curve (AUC 0 → ∞ ) was dose proportional, and the mean maximum plasma concentration ( C max ) increased linearly in a less than dose-proportional manner. Amprenavir was eliminated relatively slowly, with a mean terminal-phase half-life ( t 1/2 ) of 6.17 to 8.28 h. The t 1/2 , apparent total clearance, and apparent volume of distribution during the elimination phase were dose independent. Considerable interpatient variability was seen for all pharmacokinetic parameters of Amprenavir. The results of this study suggest that 20 mg of Amprenavir/kg administered twice a day should be used in future pediatric studies.
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pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with Amprenavir in opioid dependent subjects
Pharmacotherapy, 2004Co-Authors: Craig W. Hendrix, Mary Beth Wire, Yu Lou, John Wakeford, George E. Bigelow, Elizabeth A. Martinez, Jared Christopher, Edward J. Fuchs, J. SnidowAbstract:Study Objective. To investigate the steady-state pharmacokinetics of methadone enantiomers when coadministered with Amprenavir. Design. Prospective, open-label, within-subject pharmacokinetic study. Setting. University research center. Subjects. Nineteen opioid-dependent, methadone-maintained, healthy individuals were enrolled. Intervention. On study day 1, subjects received their usual once-daily dose of methadone alone. On study days 2–11, they received the same once-daily methadone dose plus Amprenavir 1200 mg twice/day Serial blood samples were collected over 24 hours on study days 1 and 11 for measurement of plasma R- and S-methadone, and over 12 hours on day 11 for serum Amprenavir concentrations. Measurements and Main Results. Standard pharmacokinetic parameters were determined from the concentrations and compared between the two treatments (methadone alone vs methadone with Amprenavir). Subjects served as their own control for methadone comparisons, and Amprenavir comparisons were made by using a historic control group (38 healthy men). Opioid-effect measures were assessed throughout the study. Coadministration of Amprenavir with methadone resulted in a 3–4-hour delay in plasma R- and S-methadone enantiomer peak concentrations at steady state (Cmax-ss). The active R-methadone enantiomer area under the plasma concentration–time curve during a dosing interval (AUCτ-ss), Cmax-ss, and the minimum plasma concentration at steady state (Cmin-ss) were decreased by 13%, 25%, and 21%, respectively, after coadministration of methadone and Amprenavir. The inactive S-enantiomer AUCτ-ss, Cmax-ss, and Cmin-ss were decreased by 40%, 48%, and 52%, respectively. No clinically significant changes were noted in opioid pharmacodynamic effects, and there was no evidence of opioid withdrawal. No methadone dosage was changed in any subject. Conclusion. No a priori adjustment in methadone dosage is required during coadministration with Amprenavir as there is only a small effect on R-methadone exposure and no evidence of opioid withdrawal.
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Pharmacokinetics and Pharmacodynamics of Methadone Enantiomers After Coadministration with Amprenavir in Opioid‐Dependent Subjects
Pharmacotherapy, 2004Co-Authors: Craig W. Hendrix, Mary Beth Wire, Yu Lou, John Wakeford, George E. Bigelow, Elizabeth A. Martinez, Jared Christopher, Edward J. Fuchs, J. SnidowAbstract:Study Objective. To investigate the steady-state pharmacokinetics of methadone enantiomers when coadministered with Amprenavir. Design. Prospective, open-label, within-subject pharmacokinetic study. Setting. University research center. Subjects. Nineteen opioid-dependent, methadone-maintained, healthy individuals were enrolled. Intervention. On study day 1, subjects received their usual once-daily dose of methadone alone. On study days 2–11, they received the same once-daily methadone dose plus Amprenavir 1200 mg twice/day Serial blood samples were collected over 24 hours on study days 1 and 11 for measurement of plasma R- and S-methadone, and over 12 hours on day 11 for serum Amprenavir concentrations. Measurements and Main Results. Standard pharmacokinetic parameters were determined from the concentrations and compared between the two treatments (methadone alone vs methadone with Amprenavir). Subjects served as their own control for methadone comparisons, and Amprenavir comparisons were made by using a historic control group (38 healthy men). Opioid-effect measures were assessed throughout the study. Coadministration of Amprenavir with methadone resulted in a 3–4-hour delay in plasma R- and S-methadone enantiomer peak concentrations at steady state (Cmax-ss). The active R-methadone enantiomer area under the plasma concentration–time curve during a dosing interval (AUCτ-ss), Cmax-ss, and the minimum plasma concentration at steady state (Cmin-ss) were decreased by 13%, 25%, and 21%, respectively, after coadministration of methadone and Amprenavir. The inactive S-enantiomer AUCτ-ss, Cmax-ss, and Cmin-ss were decreased by 40%, 48%, and 52%, respectively. No clinically significant changes were noted in opioid pharmacodynamic effects, and there was no evidence of opioid withdrawal. No methadone dosage was changed in any subject. Conclusion. No a priori adjustment in methadone dosage is required during coadministration with Amprenavir as there is only a small effect on R-methadone exposure and no evidence of opioid withdrawal.
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Pharmacokinetic Study of Human Immunodeficiency Virus Protease Inhibitors Used in Combination with Amprenavir
Antimicrobial agents and chemotherapy, 2001Co-Authors: Brian M. Sadler, Catherine Gillotin, Joseph J. Eron, Yu Lou, Richard Haubrich, William Lang, Daniel S. SteinAbstract:In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of Amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that Amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUC ss ] and 37% for peak plasma concentration at steady state [ C max,ss ]) and increased by indinavir (33% for AUC ss ). Nelfinavir significantly increased Amprenavir minimum drug concentration at steady state (by 189%) but did not affect Amprenavir AUC ss or C max,ss . Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with Amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with Amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in Amprenavir steady-state pharmacokinetic parameters, relative to those for Amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.
Daniel S. Stein - One of the best experts on this subject based on the ideXlab platform.
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In Vitro-In Vivo Model for Evaluating the Antiviral Activity of Amprenavir in Combination with Ritonavir Administered at 600 and 100 Milligrams, Respectively, Every 12 Hours
Antimicrobial agents and chemotherapy, 2003Co-Authors: Sandra L. Preston, William T. Symonds, Daniel S. Stein, Peter J. Piliero, J. A. Bilello, George L. DrusanoAbstract:The study objective was to evaluate the pharmacodynamics of Amprenavir in an in vitro system, develop an exposure target for maximal viral suppression, and determine the likelihood of target attainment based on the pharmacokinetics of Amprenavir and ritonavir in human immunodeficiency virus (HIV)-infected patients. Population pharmacokinetic data were obtained from 13 HIV-infected patients receiving Amprenavir and ritonavir in doses of 600 and 100 mg, respectively, every 12 h. A 2,500-subject Monte Carlo simulation was performed. Target attainment was also estimated for a target derived from clinical data. Maximal viral suppression (in vitro) was achieved when Amprenavir free-drug concentrations remained greater than four times the 50% effective concentration (EC 50 ) for 80% of the dosing interval. At an Amprenavir EC 50 of 0.03 μM, the likelihood of target attainment is 97.4%. For reduced-susceptibility isolates for which the EC 50 s are 0.05 and 0.08 μM, target attainment is 91.0 and 75.8%, respectively. For the clinical target of a trough concentration/EC 50 ratio of 5, the target attainment rates were similar. Treatment with Amprenavir and ritonavir at doses of 600 and 100 mg, respectively, twice a day provides excellent suppression of wild-type isolates and reduced-susceptibility isolates up to an EC 50 of 0.05 μM. Even at 0.12 μM, target attainment likelihood exceeds 50%, making this an option for patients with extensive exposure to protease inhibitors when this treatment is used with additional active antiretroviral agents.
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Pharmacokinetic Modeling and Simulations of Interaction of Amprenavir and Ritonavir
Antimicrobial agents and chemotherapy, 2002Co-Authors: Mark Sale, Brian M. Sadler, Daniel S. SteinAbstract: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 (Emax) 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 (Cmin) in twice-daily and once-daily dosing regimens were compared with protein binding-adjusted 50% inhibitory concentrations (IC50s) 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 Cmin-to-IC50 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 IC50s for wild-type virus are clearly feasible.
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Pharmacokinetic Study of Human Immunodeficiency Virus Protease Inhibitors Used in Combination with Amprenavir
Antimicrobial agents and chemotherapy, 2001Co-Authors: Brian M. Sadler, Catherine Gillotin, Joseph J. Eron, Yu Lou, Richard Haubrich, William Lang, Daniel S. SteinAbstract:In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of Amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that Amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUC ss ] and 37% for peak plasma concentration at steady state [ C max,ss ]) and increased by indinavir (33% for AUC ss ). Nelfinavir significantly increased Amprenavir minimum drug concentration at steady state (by 189%) but did not affect Amprenavir AUC ss or C max,ss . Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with Amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with Amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in Amprenavir steady-state pharmacokinetic parameters, relative to those for Amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.
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In Vivo Effect of α1-Acid Glycoprotein on Pharmacokinetics of Amprenavir, a Human Immunodeficiency Virus Protease Inhibitor
Antimicrobial agents and chemotherapy, 2001Co-Authors: Brian M. Sadler, Catherine Gillotin, Yu Lou, Daniel S. SteinAbstract:Observations from early clinical pharmacology studies of Amprenavir, an inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that is highly bound to human plasma proteins (∼90%), showed the single-dose pharmacokinetics of Amprenavir to be variable between and within individuals. A cross-study analysis of various demographic, laboratory, and clinical covariates was therefore performed. Differences in Amprenavir pharmacokinetics could be due to variable concentrations in α 1 -acid glycoprotein (AAG), the predominant plasma protein to which Amprenavir binds. Therefore, AAG was considered an important factor to study since the literature suggested that AAG levels vary by race, age, and weight and following trauma or infection, including HIV disease. Pooled data from three single-dose studies analyzed by stepwise linear regression indicated that AAG concentrations significantly correlated with age and race and that only AAG concentrations were a significant predictor of Amprenavir apparent total clearance (CL/F). A significant inverse linear relationship was found between AAG and Amprenavir CL/F. Compared to white subjects, black subjects had significantly lower AAG concentrations and therefore significantly higher Amprenavir CL/F. Although AAG has a significant influence on the variability of total drug pharmacokinetics, unbound, or free, drug concentrations are not affected by AAG concentrations. Incorrect conclusions could be drawn on the pharmacokinetics of highly protein-bound drugs if AAG concentration is not included in the analysis.
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Pharmacokinetic Interaction between Amprenavir and Rifabutin or Rifampin in Healthy Males
Antimicrobial agents and chemotherapy, 2001Co-Authors: Ronald E. Polk, Brian M. Sadler, Donald F. Brophy, D S Israel, Roberto L. Patron, Gregory E. Chittick, William T. Symonds, Yu Lou, Debbie Kristoff, Daniel S. SteinAbstract:The objective of this study was to determine if there is a pharmacokinetic interaction when Amprenavir is given with rifabutin or rifampin and to determine the effects of these drugs on the erythromycin breath test (ERMBT). Twenty-four healthy male subjects were randomized to one of two cohorts. All subjects received Amprenavir (1,200 mg twice a day) for 4 days, followed by a 7-day washout period, followed by either rifabutin (300 mg once a day [QD]) (cohort 1) or rifampin (600 mg QD) (cohort 2) for 14 days. Cohort 1 then received Amprenavir plus rifabutin for 10 days, and cohort 2 received Amprenavir plus rifampin for 4 days. Serial plasma and urine samples for measurement of Amprenavir, rifabutin, and rifampin and their 25-O-desacetyl metabolites, were measured by high-performance liquid chromatography. Rifabutin did not significantly affect Amprenavir's pharmacokinetics. Amprenavir significantly increased the area under the curve at steady state (AUCss) of rifabutin by 2.93-fold and the AUCss of 25-O-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUCss of Amprenavir by 82%, but Amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decreased the results of the ERMBT by 83%. The results of the ERMBT after 2 weeks of rifabutin and rifampin therapy were increased 187 and 156%, respectively. Amprenavir plus rifampin was well tolerated. Amprenavir plus rifabutin was poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin markedly increases the metabolic clearance of Amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabutin and 25-O-desacetylrifabutin, and the combination is poorly tolerated. Amprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent inducers of the ERMBT.
Anne-marie Taburet - One of the best experts on this subject based on the ideXlab platform.
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Predictive values of the human immunodeficiency virus phenotype and genotype and of Amprenavir and lopinavir inhibitory quotients in heavily pretreated patients on a ritonavir-boosted dual-protease-inhibitor regimen.
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Aurélie Barrail-tran, Laurence Morand-joubert, Gwendoline Poizat, Gilles Raguin, Clotilde Le Tiec, Pierre Marie Girard, Genevieve Chene, Francois Clavel, Elisabeth Dam, Anne-marie TaburetAbstract:The inhibitory quotient (IQ) of human immunodeficiency virus (HIV) protease inhibitors (PIs), which is the ratio of drug concentration to viral susceptibility, is considered to be predictive of the virological response. We used several approaches to calculate the IQs of Amprenavir and lopinavir in a subset of heavily pretreated patients participating in the French National Agency for AIDS Research (ANRS) 104 trial and then compared their potentials for predicting changes in the plasma HIV RNA level. Thirty-seven patients were randomly assigned to receive either Amprenavir (600 mg twice a day [BID]) or lopinavir (400 mg BID) plus ritonavir (100 or 200 mg BID) for 2 weeks before combining the two PIs. The 90% inhibitory concentration (IC(90)) was measured using a recombinant assay without or with additional human serum (IC(90+serum)). Total and unbound PI concentrations in plasma were measured. Univariate linear regression was used to estimate the relation between the change in viral load and the IC(90) or IQ values. The Amprenavir phenotypic IQ values were very similar when measured with the standard and protein binding-adjusted IC(90)s. No relationship was found between the viral load decline and the lopinavir IQ. During combination therapy, the Amprenavir and lopinavir genotypic IQ values were predictive of the viral response at week 6 (P = 0.03). The number of protease mutations (/=5) was related to the virological response throughout the study. These findings suggest that the combined genotypic IQ and the number of protease mutations are the best predictors of virological response. High Amprenavir and lopinavir concentrations in these patients might explain why plasma concentrations and the phenotypic IQ have poor predictive value.
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Predictive Values of the Human Immunodeficiency Virus Phenotype and Genotype and of Amprenavir and Lopinavir Inhibitory Quotients in Heavily Pretreated Patients on a Ritonavir-Boosted Dual-Protease-Inhibitor Regimen
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Aurélie Barrail-tran, Laurence Morand-joubert, Gwendoline Poizat, Gilles Raguin, Clotilde Le Tiec, Pierre Marie Girard, Genevieve Chene, Francois Clavel, Anne-marie TaburetAbstract:The inhibitory quotient (IQ) of human immunodeficiency virus (HIV) protease inhibitors (PIs), which is the ratio of drug concentration to viral susceptibility, is considered to be predictive of the virological response. We used several approaches to calculate the IQs of Amprenavir and lopinavir in a subset of heavily pretreated patients participating in the French National Agency for AIDS Research (ANRS) 104 trial and then compared their potentials for predicting changes in the plasma HIV RNA level. Thirty-seven patients were randomly assigned to receive either Amprenavir (600 mg twice a day [BID]) or lopinavir (400 mg BID) plus ritonavir (100 or 200 mg BID) for 2 weeks before combining the two PIs. The 90% inhibitory concentration (IC90) was measured using a recombinant assay without or with additional human serum (IC90+serum). Total and unbound PI concentrations in plasma were measured. Univariate linear regression was used to estimate the relation between the change in viral load and the IC90 or IQ values. The Amprenavir phenotypic IQ values were very similar when measured with the standard and protein binding-adjusted IC90s. No relationship was found between the viral load decline and the lopinavir IQ. During combination therapy, the Amprenavir and lopinavir genotypic IQ values were predictive of the viral response at week 6 (P = 0.03). The number of protease mutations (
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Salvage therapy with Amprenavir, lopinavir and ritonavir is durably potent in HIV-infected patients in virological failure: 1-year results.
AIDS (London England), 2007Co-Authors: Gilles Raguin, Laurence Morand-joubert, Gwendoline Poizat, Clotilde Le Tiec, Genevieve Chene, Francois Clavel, Anne-marie Taburet, Pierre Marie GirardAbstract:We report the results of the extended follow-up at one year of a randomized trial evaluating the virological efficacy of a salvage therapy combining lopinavir and Amprenavir with either 200 or 400 mg/day ritonavir, along with optimized nucleoside reverse transcriptase inhibitors, in patients carrying multidrug-resistant isolates. The combination of Amprenavir, lopinavir and ritonavir (400 mg/day) is durably potent, yielding a sustained virological response (HIV RNA < 50 copies) in 39% of cases.
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Determination of Amprenavir total and unbound concentrations in plasma by high-performance liquid chromatography and ultrafiltration.
Therapeutic drug monitoring, 2006Co-Authors: Aurélie Barrail, Clotilde Le Tiec, Isabelle Vincent, Sabine Paci-bonaventure, Valérie Furlan, Anne-marie TaburetAbstract:Amprenavir is an HIV-1 protease inhibitor with high protein binding (90%) in human plasma. This study was designed to develop an assay to measure the concentration of unbound Amprenavir, to study variation with time in patients, and to investigate whether ritonavir and lopinavir, other protease inhibitors that could be combined, interact with Amprenavir protein binding in vitro. A reverse-phase high-performance liquid chromatography assay to UV detection was developed and validated to measure total Amprenavir in plasma, and this method was adapted to quantitate low concentrations of unbound Amprenavir in ultrafiltrate aqueous fluid. Equilibrium dialysis and ultrafiltration were used and compared with separate unbound fraction. The latter method was easier to use and was, therefore, subsequently adopted. In 10 patients who received Amprenavir 600 mg bid combined with ritonavir, mean Amprenavir free-fraction in plasma was 8.6% (range, 4.4-20%). When added to pooled human plasmas at concentrations close to those found in treated patients, the unbound Amprenavir fraction was increased in the presence of lopinavir, but remained unaffected by ritonavir. It remains to be seen whether measurement of unbound concentrations, rather than total concentrations, could improve therapeutic drug monitoring.
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Interactions between Amprenavir and the lopinavir-ritonavir combination in heavily pretreated patients infected with human immunodeficiency virus.
Clinical pharmacology and therapeutics, 2004Co-Authors: Anne-marie Taburet, Laurence Morand-joubert, Gilles Raguin, Clotilde Le Tiec, Genevieve Chene, Francois Clavel, Isabelle Vincent, Aurélie Barrail, Cécile Droz, Pierre Marie GirardAbstract:Objective This pharmacokinetic study was designed to characterize interactions between Amprenavir and the lopinavir-ritonavir combination in patients infected with human immunodeficiency virus in whom previous antiretroviral therapy had failed. Methods Twenty-seven patients included in a randomized clinical trial (ANRS [National Agency for AIDS Research] Protocol 104) participated in this study. They were randomized to receive ritonavir at a dose of either 100 mg twice daily or 200 mg twice daily. For the first 2 weeks of therapy, they were randomly assigned to receive lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily), Amprenavir (600 mg twice daily) plus ritonavir (100 mg twice daily), lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily) plus additional ritonavir (100 mg twice daily), or Amprenavir (600 mg twice daily) plus ritonavir (200 mg twice daily). From week 3 onward, all patients received Amprenavir plus lopinavir-ritonavir with or without an additional ritonavir dose (100 mg twice daily). The pharmacokinetics of the 3 drugs was studied in weeks 2 and 6 of therapy. Results Median Amprenavir concentrations decreased by 54% (P = .004) when lopinavir was added to the Amprenavir-ritonavir regimen. Lopinavir weakly displaced Amprenavir from plasma proteins: The average unbound fraction of Amprenavir was 0.089 in week 2 and 0.114 in week 6 (P = .03), but this did not fully account for the observed interaction. Increasing the ritonavir dose did not affect the Amprenavir concentration. The relationship between lopinavir and ritonavir concentrations fitted a maximum effect (Emax) model;the average concentration of ritonavir that yielded a lopinavir concentration of 8119 ng/mL (50% of Emax) was 602 ng/mL (coefficient of variation, 22%). There was a significant relationship between the lopinavir inhibitory quotient and the virologic response in week 2 (P = .005). Conclusion Lopinavir markedly decreases the Amprenavir concentration during Amprenavir and lopinavir-ritonavir combination therapy. The inhibitory quotients were more predictive of the short-term virologic response than was the level of drug exposure. Clinical Pharmacology & Therapeutics (2004) 75, 310–323; doi:10.1016/j.clpt.2003.12.013
