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David M Burger - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of reduced dose Indinavir ritonavir 400 100 mg twice daily in hiv 1 infected thai patients
Antiviral Therapy, 2005Co-Authors: Mark A Boyd, David M Burger, Apicha Mahanontharit, Sasiwimol Ubolyam, Piroon Mootsikapun, Theshinee Chuenyam, Jongkol Sangkote, Parichart Bunyaprawit, Manasinee Horsakulchai, Joep M A LangeAbstract:OBJECTIVE: To study the pharmacokinetics of Indinavir/ ritonavir 400/100 mg twice daily in antiretroviral-naive patients at Srinagarind Hospital in Khon Kaen, Thailand. METHODS: This was a steady-state, open-label pharmacokinetic study of 19 patients. A 12 h pharmacokinetic curve was recorded after an overnight fast. Plasma levels of Indinavir and ritonavir were determined by a validated HPLC method. Virological failure was defined according to the most recent US Department of Health and Human Services guidelines as a viral load above 400 copies/ml at week 24. RESULTS: Median baseline values for CD4 and viral load were 13cells/mm3 and 167000 copies/ml, respectively. The median (interquartile ranges) for Indinavir AUC, Cmax and Cmin were 18.1 (15.3-23.8) mg/l x h, 4.1 (3.6-4.8) mg/l and 0.17 (0.12-0.30) mg/l, respectively. These values represent 37%, 39% and 24% of the AUC, Cmax and Cmin values found, respectively, for the Indinavir/ritonavir 800/100 mg dose in HIV-1-infected Thai patients. Short-term virological response was satisfactory. There were three subjects with an Indinavir Cmin. below the target value of 0.10 mg/l, of whom one had virological failure (33%). Among the other 16 subjects with an Indinavir Cmin above 0.10 mg/l, there was also one virological failure (6%) (P=0.30). CONCLUSIONS: Indinavir exposure in this reduced-dose regimen of 400 mg with 100 mg ritonavir twice daily was more than dose-proportionally lower than previously observed with the Indinavir/ritonavir 800/100 mg twice daily regimen. Therapeutic Cmin levels of Indinavir were achieved in >80% of the subjects and short-term virological response was satisfactory in this cohort of patients starting highly active antiretroviral therapy at an advanced disease stage with high baseline viral loads.
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therapeutic drug monitoring of nelfinavir and Indinavir in treatment naive hiv 1 infected individuals
AIDS, 2003Co-Authors: David M Burger, Inge C Gyssens, P W H Hugen, Peter Reiss, Kees Brinkman, Gerrit Schreij, Michaela Schneider, F P Kroon, Clemens Richter, Jan M PrinsAbstract:Background: Both virological failure and the toxicity of HIV protease inhibitors have been related to interindividual variability of plasma drug concentrations. Therapeutic drug monitoring (TDM) offers the possibility to detect patients with drug concentrations outside therapeutic ranges, who can subsequently benefit from dose modifications. Methods: ATHENA was a randomized controlled clinical trial. Subjects were randomly assigned to either a TDM group, in which the results of drug concentration measurements plus advice were reported to their treating physician, or to a control group for whom TDM results were not reported. This analysis refers to treatment-naive patients who started a regimen containing Indinavir or nelfinavir before November 1999. Findings: A total of 147 patients were randomly assigned: 92 to nelfinavir, 55 to Indinavir. After one year of follow-up significantly fewer patients in the TDM group had discontinued nelfinavir or Indinavir than in the control group: 17.4 versus 39.7%. This was mainly driven by a significantly lower rate of discontinuation because of virological failure in nelfinavir patients: 2.4% in the TDM group versus 17.6% in the control group, and by a non-significant difference in the rate of discontinuation because of toxicity in Indinavir patients: 14.3% in the TDM group versus 29.6% in the control group. In a non-completer equals failure analysis of all randomized patients, the TDM group showed a significantly higher proportion of patients with a viral load below 500 copies after 12 months of treatment (78.2 versus 55.1%). Interpretation: TDM of nelfinavir and Indinavir in treatment-naive patients improves treatment response.
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pharmacokinetics and pharmacodynamics of Indinavir with or without low dose ritonavir in hiv infected thai patients
Journal of Antimicrobial Chemotherapy, 2003Co-Authors: David M Burger, David A Cooper, Michael Stek, Mark A Boyd, Chris Duncombe, Mariet Felderhof, Apicha Mahanontharit, Kiat Ruxrungtham, Sasiwimol Ubolyam, Joep M A LangeAbstract:Objectives: To describe the pharmacokinetics and pharmacodynamics of Indinavir with or without low-dose ritonavir in human immunodeficiency virus (HIV)-infected Thai patients. Patients and methods: Thirty-six HIV-1-infected patients who participated in HIV-NAT 005 study gave informed consent to record a pharmacokinetic curve 4 weeks after starting a regimen containing either Indinavir 800 mg every 8 h (n = 19) or Indinavir 800 mg + ritonavir 100 mg every 12 h (n = 17). Indinavir plasma concentrations were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods. Results: The median (interquartile range; IQR) body weight of the 36 patients (11 females and 25 males) was 60 (54-72) kg. Median and IQR values for Indinavir AUC, C max and C min were 20.9 (13.1-27.0) mg.h/L, 8.1 (6.6-9.4) mg/L and 0.13 (0.09-0.27) mg/L, respectively, for Indinavir 800 mg every 8 h, and 49.2 (42.5-60.4) mg.h/L, 10.6 (8.5-13.2) mg/L and 0.68 (0.43-0.77) mg/L, respectively, for Indinavir 800 mg + ritonavir 100 mg every 12 h. These values are not largely different from values found in Caucasian patients, with the exception of relatively high peak levels of Indinavir in Thai subjects. Cut-off values for optimal virological efficacy were an Indinavir C min of 0.10 and 0.25 mg/L for the every 8 h and the every 12 h regimen, respectively; patients with an Indinavir AUC greater than 30 (every 8 h regimen) or 60 (every 12 h regimen) mg.h/L were at increased risk of developing nephrotoxicity. Conclusions: Indinavir pharmacokinetics and pharmacodynamics in Thai HIV-1-infected patients are similar to those described in Caucasian patients, despite an overall lower body weight in this population.
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the influence of efavirenz on the pharmacokinetics of a twice daily combination of Indinavir and low dose ritonavir in healthy volunteers
Clinical Pharmacology & Therapeutics, 2002Co-Authors: Rob E Aarnoutse, Karin J T Grintjes, D S C Telgt, Michael Stek, P W H Hugen, Peter Reiss, P P Koopmans, Y A Hekster, David M BurgerAbstract:OBJECTIVE: This study evaluated the effect of multiple-dose efavirenz on the steady-state pharmacokinetics of the combination of Indinavir (800 mg) and low-dose ritonavir (100 mg) twice a day, in which ritonavir is used to increase Indinavir plasma concentrations. METHODS: Eighteen healthy male volunteers participated in this multiple-dose, 1-arm, 2-period interaction study. They took a combination of 800 mg Indinavir and 100 mg ritonavir with food for 15 days. From days 15 to 29, a once-daily administration of 600 mg efavirenz was added to the combination. Pharmacokinetics of Indinavir and ritonavir on days 15 and 29 were compared. RESULTS: Fourteen volunteers completed the study. The addition of efavirenz resulted in significant reductions (P <.01) in Indinavir area under the curve (AUC, -25%), trough concentration (C(min), -50%), and maximum concentration (C(max), -17%). All Indinavir C(min) levels on day 29 remained equivalent to or above the mean C(min) value described for the regimen of 800 mg Indinavir three times a day, without ritonavir (0.15 mg/L). Changes in ritonavir AUC, C(min), and C(max) were -36%, -39%, and -34%, respectively. Pharmacokinetics of efavirenz on day 29 were comparable with published data. CONCLUSIONS: The addition of efavirenz to a combination of 800 mg Indinavir and 100 mg ritonavir twice daily results in significant decreases in AUC, C(max), and especially C(min) of Indinavir. The dose of Indinavir or ritonavir should be increased to maintain similar Indinavir drug levels after addition of efavirenz to the Indinavir-ritonavir combination. Dose modifications may not be needed in antiretroviral-naive human immunodeficiency virus-infected patients if the reference C(min) of the regimen of 800 mg Indinavir 3 times a day is considered to be adequate.
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urological complaints in relation to Indinavir plasma concentrations in hiv infected patients
AIDS, 1999Co-Authors: Jeanne P Dieleman, Inge C Gyssens, M E Van Der Ende, S De Marie, David M BurgerAbstract:Objective: To assess the relationship between Indinavir-associated urological complaints and Indinavir plasma concentrations. Design: Case series, comparing Indinavir plasma concentrations in cases with average concentrations in a control group. Methods: Patients taking 800 mg Indinavir three times a day (tid), who presented with overt urological complaints (renal colic, flank pain or haematuria) were selected for the study. Plasma Indinavir concentrations were measured by means of a standardized high performance liquid chromatography (HPLC) method. Plasma samples taken at 1.5-8 h after the last Indinavir ingestion were included for evaluation. Results were compared with the full pharmacokinetic curves of Indinavir plasma concentrations from a control group of 14 patients taking 800 mg Indinavir tid without urological complaints, and were expressed as concentration ratios. A ratio of 1 indicated a plasma concentration equalling the average concentration in the control population at the same point in time after the ingestion of Indinavir. Results: Seventeen patients (five women) were enrolled and the Indinavir concentrations of 15 patients could be evaluated. Fourteen (93%) patients had a concentration above the mean of the controls, 12 (80%) patients had a concentration above the upper 95% confidence limit, and one (7%) patient had a concentration below the lower 95% confidence limit. The mean Indinavir concentration in patients with urological complaints (ratio range 0.55-11.49) was significantly higher than the average concentration and the upper 95% confidence limit of the control group (P < 0.05). The results could not be explained by differences in weight, sex or drug interactions. Two patients had chronic active hepatitis B infection. In six patients with Indinavir concentrations above the upper 95% limit, Indinavir was reduced to 600 mg tid. Upon repeat measurement after the dose adjustment, their Indinavir plasma concentrations fell within the 95% confidence interval around the mean of the control population. All six patients remained asymptomatic and had viral loads of less than 500 copies per ml after a follow-up of 5-16 months. Conclusions: Urological complications occurring during Indinavir treatment were associated with elevated Indinavir plasma concentrations in 80% of patients in this study. Indinavir plasma concentrations should be monitored upon presentation of urological complaints, on the basis of which dose reductions may be applied if brief interruption and increased hydration are ineffective.
Joep M A Lange - One of the best experts on this subject based on the ideXlab platform.
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relationship between hyperbilirubinaemia and udp glucuronosyltransferase 1a1 ugt1a1 polymorphism in adult hiv infected thai patients treated with Indinavir
Pharmacogenetics and Genomics, 2006Co-Authors: Mark A Boyd, Joep M A Lange, David A Cooper, Michael Stek, Kiat Ruxrungtham, Preeyaporn Srasuebkul, Peter I Mackenzie, Verawan Uchaipichat, Praphan Phanuphak, Wandee UdomuksornAbstract:ObjectivesTo investigate the association between the UGT1A1*6 (G71R) and UGT1A1*28 (promoter (TA)7-repeat) genotypes and hyperbilirubinaemia in Thai patients treated with Indinavir, and characterize the inhibition of human UGTs by Indinavir in vitro.MethodsNinety-six Thai HIV patients receiving indi
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pharmacokinetics of reduced dose Indinavir ritonavir 400 100 mg twice daily in hiv 1 infected thai patients
Antiviral Therapy, 2005Co-Authors: Mark A Boyd, David M Burger, Apicha Mahanontharit, Sasiwimol Ubolyam, Piroon Mootsikapun, Theshinee Chuenyam, Jongkol Sangkote, Parichart Bunyaprawit, Manasinee Horsakulchai, Joep M A LangeAbstract:OBJECTIVE: To study the pharmacokinetics of Indinavir/ ritonavir 400/100 mg twice daily in antiretroviral-naive patients at Srinagarind Hospital in Khon Kaen, Thailand. METHODS: This was a steady-state, open-label pharmacokinetic study of 19 patients. A 12 h pharmacokinetic curve was recorded after an overnight fast. Plasma levels of Indinavir and ritonavir were determined by a validated HPLC method. Virological failure was defined according to the most recent US Department of Health and Human Services guidelines as a viral load above 400 copies/ml at week 24. RESULTS: Median baseline values for CD4 and viral load were 13cells/mm3 and 167000 copies/ml, respectively. The median (interquartile ranges) for Indinavir AUC, Cmax and Cmin were 18.1 (15.3-23.8) mg/l x h, 4.1 (3.6-4.8) mg/l and 0.17 (0.12-0.30) mg/l, respectively. These values represent 37%, 39% and 24% of the AUC, Cmax and Cmin values found, respectively, for the Indinavir/ritonavir 800/100 mg dose in HIV-1-infected Thai patients. Short-term virological response was satisfactory. There were three subjects with an Indinavir Cmin. below the target value of 0.10 mg/l, of whom one had virological failure (33%). Among the other 16 subjects with an Indinavir Cmin above 0.10 mg/l, there was also one virological failure (6%) (P=0.30). CONCLUSIONS: Indinavir exposure in this reduced-dose regimen of 400 mg with 100 mg ritonavir twice daily was more than dose-proportionally lower than previously observed with the Indinavir/ritonavir 800/100 mg twice daily regimen. Therapeutic Cmin levels of Indinavir were achieved in >80% of the subjects and short-term virological response was satisfactory in this cohort of patients starting highly active antiretroviral therapy at an advanced disease stage with high baseline viral loads.
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Effect of Mycophenolate Mofetil on the Pharmacokinetics of Antiretroviral Drugs and on Intracellular Nucleoside Triphosphate Pools
Clinical Pharmacokinetics, 2004Co-Authors: Sanjay U. C. Sankatsing, Joep M A Lange, Jos H Beijnen, Patrick G. Hoggard, Alwin D. R. Huitema, Rolf W. Sparidans, Stephen Kewn, Kristel M. L. Crommentuyn, David J. Back, Jan M PrinsAbstract:Objective To study the effect of mycophenolate mofetil therapy on the pharmacokinetic parameters of a number of antiretroviral drugs, on intracellular pools of deoxycytidine triphosphate (dCTP) and deoxyguanosine triphosphate (dGTP), and on intracellular concentrations of the triphosphate of lamivudine (3TCTP). Design Randomised pharmacokinetic study. Participants Nineteen HIV-1-infected patients. Methods Antiretroviral-naive men starting treatment with didanosine 400mg once daily, lamivudine 150mg twice daily, abacavir 300mg twice daily, Indinavir 800mg twice daily, ritonavir 100mg twice daily and nevirapine 200mg twice daily were randomised to a group with or without mycophenolate mofetil 500mg twice daily. After 8 weeks of therapy, the plasma pharmacokinetic profiles of mycophenolic acid (the active metabolite of mycophenolate mofetil), abacavir, Indinavir and nevirapine, and triphosphate concentrations (dCTP, dGTP and 3TCTP) in peripheral blood mononuclear cells, were determined. Results Nine of the 19 patients received mycophenolate mofetil. There was no difference in plasma clearance of Indinavir or abacavir between the two groups. The clearance of nevirapine was higher in patients using mycophenolate mofetil (p = 0.04). In 12 patients, of whom five also received mycophenolate mofetil, intracellular triphosphates were measured. There was no significant difference in intracellular dCTP, dGTP or 3TCTP concentrations between the two groups. Conclusion : In this small cohort of patients, mycophenolate mofetil therapy reduced the plasma concentration of nevirapine but had no effect on plasma concentrations of Indinavir and abacavir. There were no consistent effects of mycophenolic acid on the intracellular concentrations of dCTP, dGTP or 3TCTP.
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pharmacokinetics and pharmacodynamics of Indinavir with or without low dose ritonavir in hiv infected thai patients
Journal of Antimicrobial Chemotherapy, 2003Co-Authors: David M Burger, David A Cooper, Michael Stek, Mark A Boyd, Chris Duncombe, Mariet Felderhof, Apicha Mahanontharit, Kiat Ruxrungtham, Sasiwimol Ubolyam, Joep M A LangeAbstract:Objectives: To describe the pharmacokinetics and pharmacodynamics of Indinavir with or without low-dose ritonavir in human immunodeficiency virus (HIV)-infected Thai patients. Patients and methods: Thirty-six HIV-1-infected patients who participated in HIV-NAT 005 study gave informed consent to record a pharmacokinetic curve 4 weeks after starting a regimen containing either Indinavir 800 mg every 8 h (n = 19) or Indinavir 800 mg + ritonavir 100 mg every 12 h (n = 17). Indinavir plasma concentrations were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods. Results: The median (interquartile range; IQR) body weight of the 36 patients (11 females and 25 males) was 60 (54-72) kg. Median and IQR values for Indinavir AUC, C max and C min were 20.9 (13.1-27.0) mg.h/L, 8.1 (6.6-9.4) mg/L and 0.13 (0.09-0.27) mg/L, respectively, for Indinavir 800 mg every 8 h, and 49.2 (42.5-60.4) mg.h/L, 10.6 (8.5-13.2) mg/L and 0.68 (0.43-0.77) mg/L, respectively, for Indinavir 800 mg + ritonavir 100 mg every 12 h. These values are not largely different from values found in Caucasian patients, with the exception of relatively high peak levels of Indinavir in Thai subjects. Cut-off values for optimal virological efficacy were an Indinavir C min of 0.10 and 0.25 mg/L for the every 8 h and the every 12 h regimen, respectively; patients with an Indinavir AUC greater than 30 (every 8 h regimen) or 60 (every 12 h regimen) mg.h/L were at increased risk of developing nephrotoxicity. Conclusions: Indinavir pharmacokinetics and pharmacodynamics in Thai HIV-1-infected patients are similar to those described in Caucasian patients, despite an overall lower body weight in this population.
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a randomized controlled trial of Indinavir zidovudine and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy
The Journal of Infectious Diseases, 1999Co-Authors: Martin S Hirsch, Joep M A Lange, Schlomo Staszewski, John W. Mellors, Bernard Hirschel, Roy T Steigbigel, Ernesto G Scerpella, Kathleen Squires, Sandy Rawlins, Anne R MeibohmAbstract:A randomized, double-blind, multicenter study of Indinavir, zidovudine, and lamivudine was conducted in 320 adults with human immunodeficiency virus type 1 (HIV-1) infection, =50 CD4 cells/mm3, and extensive prior zidovudine therapy. Patients received Indinavir, 800 mg every 8 h; zidovudine, 200 mg every 8 h, and lamivudine, 150 mg twice daily; or all 3 drugs for 24 weeks. In an intention-to-treat analysis, proportions of patients with HIV-1 RNA <500 and <50 copies/mL, respectively, at week 24 were 56% and 45% in the Indinavir-zidovudine-lamivudine group, 3% and 2% in the Indinavir group, and 0% in the zidovudine-lamivudine group. Observed mean CD4 cell increases were 95, 78, and 6 cells/mm3 in the three-, one-, and two-drug arms, respectively. Regimens were generally well tolerated. Patients with advanced HIV-1 infection benefit from triple therapy with Indinavir, zidovudine, and lamivudine, although the proportion with optimal response appeared to be lower in patients with low CD4 cell counts.
David A Cooper - One of the best experts on this subject based on the ideXlab platform.
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Summary of cohorts.
2015Co-Authors: Mykola Pinkevych, David A Cooper, Deborah Cromer, Martin Tolstrup, Andrew J. Grimm, Sharon R. Lewin, Ole S. Søgaard, Thomas A. Rasmussen, Stephen J. Kent, Anthony D. KelleherAbstract:* One subject was treated with ART early after diagnosis of unclear duration of HIV infection, the other 8 subjects were infected for 390–6574 days from diagnosis until ART begun.** Tenofovir, Emtricitibine and either Rilpiverine (n = 3) or Efavirenz (n = 4) or Raltegravir (n = 1). One subject received Zidovudine, Lamivudine and Abacavir.*** Indinavir, ritonavir, didanosine and either stavudine or lamivudine.**** zidovudine, lamivudine plus either Indinavir (n = 7) or nelfinavir (n = 1) or ritonavir (n = 1); stavudine, lamivudine plus nelfinavir (n = 2); stavudine, didanosineplus nelfinavir (n = 2); zidovudine, didanosine plus nelfinavir (n = 1).*****including 3, 4, and 5 drug regimes.Summary of cohorts.
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relationship between hyperbilirubinaemia and udp glucuronosyltransferase 1a1 ugt1a1 polymorphism in adult hiv infected thai patients treated with Indinavir
Pharmacogenetics and Genomics, 2006Co-Authors: Mark A Boyd, Joep M A Lange, David A Cooper, Michael Stek, Kiat Ruxrungtham, Preeyaporn Srasuebkul, Peter I Mackenzie, Verawan Uchaipichat, Praphan Phanuphak, Wandee UdomuksornAbstract:ObjectivesTo investigate the association between the UGT1A1*6 (G71R) and UGT1A1*28 (promoter (TA)7-repeat) genotypes and hyperbilirubinaemia in Thai patients treated with Indinavir, and characterize the inhibition of human UGTs by Indinavir in vitro.MethodsNinety-six Thai HIV patients receiving indi
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pharmacokinetics and pharmacodynamics of Indinavir with or without low dose ritonavir in hiv infected thai patients
Journal of Antimicrobial Chemotherapy, 2003Co-Authors: David M Burger, David A Cooper, Michael Stek, Mark A Boyd, Chris Duncombe, Mariet Felderhof, Apicha Mahanontharit, Kiat Ruxrungtham, Sasiwimol Ubolyam, Joep M A LangeAbstract:Objectives: To describe the pharmacokinetics and pharmacodynamics of Indinavir with or without low-dose ritonavir in human immunodeficiency virus (HIV)-infected Thai patients. Patients and methods: Thirty-six HIV-1-infected patients who participated in HIV-NAT 005 study gave informed consent to record a pharmacokinetic curve 4 weeks after starting a regimen containing either Indinavir 800 mg every 8 h (n = 19) or Indinavir 800 mg + ritonavir 100 mg every 12 h (n = 17). Indinavir plasma concentrations were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods. Results: The median (interquartile range; IQR) body weight of the 36 patients (11 females and 25 males) was 60 (54-72) kg. Median and IQR values for Indinavir AUC, C max and C min were 20.9 (13.1-27.0) mg.h/L, 8.1 (6.6-9.4) mg/L and 0.13 (0.09-0.27) mg/L, respectively, for Indinavir 800 mg every 8 h, and 49.2 (42.5-60.4) mg.h/L, 10.6 (8.5-13.2) mg/L and 0.68 (0.43-0.77) mg/L, respectively, for Indinavir 800 mg + ritonavir 100 mg every 12 h. These values are not largely different from values found in Caucasian patients, with the exception of relatively high peak levels of Indinavir in Thai subjects. Cut-off values for optimal virological efficacy were an Indinavir C min of 0.10 and 0.25 mg/L for the every 8 h and the every 12 h regimen, respectively; patients with an Indinavir AUC greater than 30 (every 8 h regimen) or 60 (every 12 h regimen) mg.h/L were at increased risk of developing nephrotoxicity. Conclusions: Indinavir pharmacokinetics and pharmacodynamics in Thai HIV-1-infected patients are similar to those described in Caucasian patients, despite an overall lower body weight in this population.
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abacavir lamivudine zidovudine vs Indinavir lamivudine zidovudine in antiretroviral naive hiv infected adults a randomized equivalence trial
JAMA, 2001Co-Authors: Schlomo Staszewski, Philip Keiser, Joe Gathe, Vitor Brotas, Scott M. Hammer, Francois Raffi, Charles B. Hicks, David A Cooper, Julio S. G. Montaner, Margaret JohnsonAbstract:ContextAbacavir, a nucleoside analogue, has demonstrated suppression of human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a standard protease inhibitor–containing regimen for initial antiretroviral treatment.ObjectiveTo evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an Indinavir-lamivudine-zidovudine regimen.Design and SettingA multicenter, phase 3, randomized, double-blind trial with an enrollment period from August 1997 to June 1998, with follow-up through 48 weeks at 73 clinical research units in the United States, Canada, Australia, and Europe.PatientsFive hundred sixty-two antiretroviral-naive, HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 × 106/L.InterventionsPatients were stratified by baseline HIV RNA level and randomly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and Indinavir placebo or 800 mg of Indinavir every 8 hours daily plus abacavir placebo. After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving randomized treatment or receive open-label therapy.Main Outcome MeasureVirologic suppression, defined as HIV RNA concentration of 400 copies/mL or less at week 48.ResultsThe proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group (51% [133/262]) and in the Indinavir group (51% [136/265]) with a treatment difference of −0.6% (95% confidence interval [CI], −9% to 8%). In patients with baseline HIV RNA levels greater than 100 000 copies/mL, the proportion of patients achieving less than 50 copies/mL was greater in the Indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96) and a treatment diference of −14% (95% CI, −27% to 0%). The 2 treatments were comparable with respect to their effects on CD4 cell count. There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities. One death in the abacavir group was attributed to hypersensitivity reaction, which occurred following rechallenge with abacavir, approximately 3 weeks after initiating study treatment.ConclusionsIn this study of antiretroviral-naive HIV-infected adults, the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of Indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks.
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a randomised open label comparison of three highly active antiretroviral therapy regimens including two nucleoside analogues and Indinavir for previously untreated hiv 1 infection the ozcombo1 study
AIDS, 2000Co-Authors: Andrew Carr, David A Cooper, John Chuah, Jeff Hudson, Martyn A French, Jennifer F Hoy, Matthew Law, D Sayer, Scan EmeryAbstract:Background: Highly active antiretroviral therapy (HAART) including two nucleoside analogues and a potent protease inhibitor is standard of care initial therapy for HIV-infected adults. The best-tolerated and most potent initial HAART regimen is unknown and was investigated in this study. Methods: One hundred and nine HIV-infected adults with no prior antiretroviral therapy, and CD4 lymphocyte counts 30 000 copies/ml were randomized to zidovudine-lamivudine-Indinavir (ZDV-3TC-IDV). stavudine-lamivudine-Indinavir (d4T-3TC-IDV) or stavudine-didanosine-Indinavir (d4T-ddl-IDV) for 52 weeks. The primary endpoints were plasma HIV RNA and drug-related adverse events. Other assessments were overall safety, adherence and adverse events, CD4 lymphocyte counts, cutaneous delayed type hypersensitivity (DTH) responses and quality of life (Euroqol). Results: Only 58% patients had HIV RNA 40% patients after only 12 months of therapy although there was significant overall improvement immunologically and in quality of life. The type of dual nucleoside combination used was less important in predicting virological failure than was imperfect adherence early in therapy. Consideration should be given to modifying a HAART regimen relatively early in non-adherent patients.
Courtney V Fletcher - One of the best experts on this subject based on the ideXlab platform.
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pharmacogenetic characteristics of Indinavir zidovudine and lamivudine therapy in hiv infected adults a pilot study
Journal of Acquired Immune Deficiency Syndromes, 2006Co-Authors: Peter L Anderson, Jatinder K Lamba, Christina L Aquilante, Erin G Schuetz, Courtney V FletcherAbstract:Objective: The aim of the study was to investigate relationships among Indinavir, lamivudine-triphosphate, and zidovudine-triphosphate pharmacokinetics and pharmacodynamics with polymorphisms in CYP3A5, MDR1, MRP2, MRP4, BCRP, and UGT1A1 genes. Study Design: Retrospective pilot investigation among 33 subjects who participated in a randomized pharmacological study of Indinavir, lamivudine, and zidovudine. Subjects were defined as genetic variant carriers or not. Relationships were investigated with multivariable regression. Indinavir clearance was adjusted for African American race; triphosphates for sex; and HIV-response for study arm, drug exposure, and baseline HIV RNA. Results: Genetically determined CYP3A5 expressors had 44% faster Indinavir oral clearance versus nonexpressors (P = 0.002). MRP2-24C/T variant carriers had 24% faster Indinavir oral clearance (P = 0.05). Lamivudine-triphosphate concentrations were elevated 20% in MRP4 T4131G variant carriers (P = 0.004). A trend for elevated zidovudine-triphosphates was observed in MRP4 G3724A variant carriers (P = 0.06). The log 10 changes in HIV RNA from baseline to week 52 were -3.7 for MDR1 2677 TT, -3.2 for GT, and -2.2 for GG (P < 0.05). Bilirubin increases were 2-fold higher in UGT1A1 [TA] 7 /[TA] 7 genotypes. No relationships were identified with BCRP. Discussion: Novel relationships were identified among genetic variants in drug transporters and Indinavir, lamivudine-triphosphate, and zidovudine-triphosphate concentrations. CYP3A5 expression was associated with faster Indinavir oral clearance. These pilot data provide a scientific basis for more rational utilization of antiretroviral drugs.
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pharmacological basis for concentration controlled therapy with zidovudine lamivudine and Indinavir
Antimicrobial Agents and Chemotherapy, 2001Co-Authors: Thomas N Kakuda, Richard C Brundage, Linda M Page, Edward P Acosta, Keith Henry, Peter L Anderson, Timothy W Schacker, Frank S Rhame, Courtney V FletcherAbstract:Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and Indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naive subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and Indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for Indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased Indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.
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pharmacologic characteristics of Indinavir didanosine and stavudine in human immunodeficiency virus infected children receiving combination therapy
Antimicrobial Agents and Chemotherapy, 2000Co-Authors: Courtney V Fletcher, Richard C Brundage, Rory P Remmel, Linda M Page, Dennis Weller, Nancy R Calles, Cara Simon, Mark W KlineAbstract:The use of human immunodeficiency virus (HIV) protease inhibitors in children has lagged behind that in adults because of the lack of suitable pediatric formulations and information on safe and effective dosing regimens. This study was designed to obtain pharmacokinetic information on Indinavir, administered to HIV-infected children also receiving therapy with two nucleoside agents, and to explore relationships between pharmacokinetic parameters and anti-HIV effect. Indinavir was initiated at a dose of 500 mg/m2 every 8 h. Plasma Indinavir concentrations were measured every 4 weeks; the dose or dosing interval was adjusted to maintain trough concentrations of ≥0.1 mg/liter. All children were evaluated clinically at baseline and every 4 weeks. Plasma HIV RNA was quantitated at baseline and at weeks 4, 12, and 24. Eighteen children participated in this study. The average daily dose of Indinavir was 2,043 mg/m2; nine children received Indinavir at 6-h intervals. Pharmacokinetic characteristics of Indinavir (mean ± standard deviation) were the following: oral clearance, 1.4 ± 0.5 liters/h/kg; half-life, 1.1 ± 0.43 h; and trough concentration, 0.29 ± 0.32 mg/liter. In nine children that completed 24 weeks of therapy, the baseline-to-week-24 change in HIV RNA level was related to Indinavir trough concentration and didanosine area under the curve. This study illustrates the ability to obtain pharmacokinetic information from children during routine clinic visits and to use this information to provide a safeguard against underdosing. The incorporation of pharmacologic knowledge with virologic, immunologic, and behavioral considerations should result in improved clinical outcomes for children infected with HIV.
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simultaneous hplc assay for quantification of Indinavir nelfinavir ritonavir and saquinavir in human plasma
Clinical Chemistry, 2000Co-Authors: Rory P Remmel, Dennis Weller, Sagar P Kawle, Courtney V FletcherAbstract:Background: HIV protease inhibitors are recommended as part of combination antiretroviral therapy. Dual protease inhibitor therapy is also being used clinically. Consequently, a simultaneous assay for Indinavir, nelfinavir, ritonavir, and saquinavir was developed. Methods: Indinavir, nelfinavir, ritonavir, and saquinavir were extracted from plasma (250 μL) with methyl- t -butyl ether at basic pH after addition of an internal standard (A-86093). The compounds were separated on a Keystone BetaBasic C4 column (250 × 3 mm i.d.) at 40 °C with a mobile phase of acetonitrile-50 mmol/L ammonium formate buffer, pH 4.1 (52:48, by volume) at a flow rate of 0.5 mL/min. Indinavir, nelfinavir, ritonavir, and the internal standard (A-86093) were detected at 218 nm, and saquinavir was detected at 235 nm. The method was validated by analysis of five triplicate analyses of calibrators along with quality-control samples at three different concentrations prepared in human plasma. Results: The extraction recovery was 87–92%. Within-run accuracy for quality-control samples was 6–8%, with CVs of 2–8%. Limits of quantification were 40–50 μg/L for Indinavir, nelfinavir, and ritonavir, and 20 μg/L for saquinavir. Cross-validation with a liquid chromatography-mass spectroscopy method for saquinavir and nelfinavir was conducted with patient samples. Regression analysis revealed a good correlation ( r 2 >0.94) between methods. Larger variations at concentrations >4000 μg/L were observed with nelfinavir. Interference with drugs commonly used in AIDS patients was not observed. Pharmacokinetic profiles for two patients on dual protease therapy were determined. Conclusions: A reliable and rugged simultaneous HPLC assay for four HIV protease inhibitors was developed. The assay method is convenient for clinical laboratories involved in therapeutic drug monitoring for HIV protease inhibitors. The assay has enough sensitivity to conduct pharmacokinetic studies in patients taking more than one HIV protease inhibitor along with other antiretroviral medications.
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Indinavir concentrations and antiviral effect
Pharmacotherapy, 1999Co-Authors: Edward P Acosta, Linda M Page, Keith Henry, Leslie Baken, Courtney V FletcherAbstract:Study Objectives. To determine the variability of Indinavir pharmacokinetics in patients attending an outpatient clinic, and to explore relationships between Indinavir exposure and antiviral effect. Design. Open, formal pharmacokinetic evaluation. Setting. University-affiliated clinical research center. Patients. Forty-three adults infected with the human immunodeficiency virus (HIV) receiving therapy with Indinavir and concomitant nucleoside reverse transcriptase inhibitors. Intervention. Indinavir concentrations were measured after patients were observed taking an 800-mg oral dose, and pharmacokinetic parameters were determined using a one-compartment oral absorption model. Virologic and pharmacologic characteristics were compared in a subset of 23 patients who were protease inhibitor naive before receiving Indinavir. Measurements and Main Results. Mean Indinavir pharmacokinetics were similar to those reported previously. Significant intersubject variability in systemic exposure was observed in patients receiving the same dosage; the 8-hour area under the curve (AUC8) ranged from 5.4–68.0 μM•hour. In protease inhibitor-naive subjects, the Indinavir AUC8 was statistically higher in those with undetectable plasma HIV RNA (30.7 μM•hr) versus detectable plasma HIV RNA (22.4 μM•hr, p=0.035). Measured concentrations 5 hours after the dose and extrapolated 8-hour concentrations were also significantly higher in patients with undetectable plasma HIV RNA (both p=0.007). Conclusions. Indinavir plasma concentrations were highly variable among patients receiving the same dosage. Patients with an undetectable plasma HIV RNA level who were protease inhibitor naive had statistically higher Indinavir concentrations and slower oral clearance than the group with detectable HIV RNA. Relationships between Indinavir concentrations and anti-HIV effect provide a basis for quantifying the pharmacologic contribution to the heterogeneity in therapeutic response.
Diane V Havlir - One of the best experts on this subject based on the ideXlab platform.
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virtual inhibitory quotient predicts response to ritonavir boosting of Indinavir based therapy in human immunodeficiency virus infected patients with ongoing viremia
Antimicrobial Agents and Chemotherapy, 2002Co-Authors: Nancy S Shulman, Andrew R. Zolopa, Diane V Havlir, Ann Hsu, Cheryl L Renz, Sheila Boller, Ping Jiang, Richard A Rode, Joel E Gallant, Elizabeth RaceAbstract:Depending on the degree of underlying resistance present, optimization of the pharmacokinetics of protease inhibitors may result in improved virologic suppression. Thirty-seven human immunodeficiency virus (HIV)-infected subjects who had chronic detectable viremia and who were receiving 800 mg of Indinavir three times a day (TID) were switched to 400 mg of Indinavir BID with 400 mg of ritonavir two times a day (BID) for 48 weeks. Full pharmacokinetic evaluations were obtained for 12 subjects before the switch and 3 weeks after the switch. Combination therapy increased the Indinavir predose concentrations in plasma by 6.47-fold, increased the minimum concentration in serum by 3.41-fold, and reduced the maximum concentration in serum by 57% without significantly changing the area under the plasma concentration-time curve at 24 h. At week 3, 58% (21 of 36) of the subjects for whom postbaseline measurements were available achieved a viral load in plasma of <50 copies/ml or a reduction from the baseline load of ≥0.5 log10 copies/ml. Of these subjects, 82% (14 of 17) whose viruses had three or fewer protease inhibitor mutations and 88% (14 of 16) whose viruses had an Indinavir virtual phenotypic susceptibility test of more than sixfold less than that for the baseline isolate were considered virologic responders. The Indinavir virtual inhibitory quotient, which is a function of baseline Indinavir phenotypic resistance (estimated by virtual phenotype) and the Indinavir predose concentration in plasma achieved with Indinavir-ritonavir combination therapy, was the best predictor of a viral load reduction. Sixteen subjects discontinued the study by week 48 due to adverse events, predominantly related to hyperlipidemia. Pharmacokinetic intensification of Indinavir-based therapy with ritonavir reduced the viral loads in subjects but added toxicity. The virtual inhibitory quotient, which incorporates both baseline viral resistance and the level of drug exposure in plasma, was superior to either baseline resistance or drug exposure alone in predicting the virologic response.
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3 year suppression of hiv viremia with Indinavir zidovudine and lamivudine
Annals of Internal Medicine, 2000Co-Authors: Roy M Gulick, John W. Mellors, Anne R Meibohm, Diane V Havlir, Joseph J Eron, Jon H Condra, Fred T Valentine, Deborah Mcmahon, Charles J Gonzalez, Leslie JonasAbstract:A three-drug regimen of Indinavir, zidovudine, and lamivudine suppressed viremia in two thirds of the 33 study patients for at least 3 years.
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drug susceptibility in hiv infection after viral rebound in patients receiving Indinavir containing regimens
JAMA, 2000Co-Authors: Diane V Havlir, Martin S Hirsch, Pablo Tebas, Ann C Collier, N S Hellmann, Christos J Petropoulos, Jeannette M Whitcomb, J P Sommadossi, Douglas D RichmanAbstract:ContextLoss of viral suppression in patients infected with human immunodeficiency virus (HIV), who are receiving potent antiretroviral therapy, has been attributed to outgrowth of drug-resistant virus; however, resistance patterns are not well characterized in patients whose protease inhibitor combination therapy fails after achieving viral suppression.ObjectiveTo characterize drug susceptibility of virus from HIV-infected patients who are failing to sustain suppression while taking an Indinavir-containing antiretroviral regimen.Design and SettingSubstudy of the AIDS Clinical Trials Group 343, a multicenter clinical research trial conducted between February 1997 and October 1998.PatientsTwenty-six subjects who experienced rebound (HIV RNA level ≥200 copies/mL) during Indinavir monotherapy (n = 9) or triple-drug therapy (Indinavir, lamivudine, and zidovudine; n = 17) after initially achieving suppression while receiving all 3 drugs, and 10 control subjects who had viral suppression while receiving triple-drug therapy.Main Outcome MeasureDrug susceptibility, determined by a phenotypic assay and genotypic evidence of resistance assessed by nucleotide sequencing of protease and reverse transcriptase, compared among the 3 patient groups.ResultsIndinavir resistance was not detected in the 9 subjects with viral rebound during Indinavir monotherapy or in the 17 subjects with rebound during triple-drug therapy, despite plasma HIV RNA levels ranging from 102 to 105 copies/mL. In contrast, lamivudine resistance was detected by phenotypic assay in rebound isolates from 14 of 17 subjects receiving triple-drug therapy, and genotypic analyses showed changes at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma Indinavir concentrations in the 2 groups with rebound were similar to those of a control group with sustained viral suppression, although levels below 50 ng/mL were more frequent in the triple-drug group than in the control group (P = .03).ConclusionsLoss of viral suppression may be due to suboptimal antiviral potency, and selection of a predominantly Indinavir-resistant virus population may be delayed for months even in the presence of ongoing Indinavir therapy. The results suggest possible value in assessing strategies using drug components of failing regimens evaluated with resistance testing.
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maintenance antiretroviral therapies in hiv infected subjects with undetectable plasma hiv rna after triple drug therapy
The New England Journal of Medicine, 1998Co-Authors: Diane V Havlir, Martin S Hirsch, Pablo Tebas, Ann C Collier, Ian C Marschner, Roland L Bassett, John P A Ioannidis, M K Holohan, Randi Y Leavitt, Gloria S BooneAbstract:Background Combination antiretroviral therapy with Indinavir, zidovudine, and lamivudine can suppress the level of human immunodeficiency virus (HIV) RNA in plasma below the threshold of detection for two years or more. We investigated whether a less intensive maintenance regimen could sustain viral suppression after an initial response to combination therapy. Methods HIV-infected subjects who had CD4 cell counts greater than 200 per cubic millimeter, who had been treated with Indinavir, lamivudine, and zidovudine, and who had less than 200 copies of HIV RNA per milliliter of plasma after 16, 20, and 24 weeks of induction therapy were randomly assigned to receive either continued triple-drug therapy (106 subjects), Indinavir alone (103 subjects), or a combination of zidovudine and lamivudine (107 subjects). The primary end point was loss of viral suppression, which was defined as a plasma level of at least 200 copies of HIV RNA per milliliter on two consecutive measurements during maintenance therapy. Res...