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David W. Haas - One of the best experts on this subject based on the ideXlab platform.

  • race ethnicity difference in the pharmacogenetics of bilirubin related Atazanavir discontinuation
    Pharmacogenetics and Genomics, 2018
    Co-Authors: Paul Leger, Lana M. Olson, Sanika Chirwa, Jacinta N Nwogu, Megan Turner, Danielle M Richardson, Paxton Baker, Michael Leonard, Husamettin Erdem, David W. Haas
    Abstract:

    Background Atazanavir causes plasma indirect bilirubin to increase. We evaluated associations between Gilbert's polymorphism and bilirubin-related Atazanavir discontinuation stratified by race/ethnicity. Patients and methods Patients had initiated Atazanavir/ritonavir-containing regimens at an HIV primary care clinic in the southeastern USA, and had at least 12 months of follow-up data. Metabolizer group was defined by UGT1A1 rs887829 C→T. Genome-wide genotype data were used to adjust for genetic ancestry in combined population analyses. Results Among 321 evaluable patients, 15 (4.6%) had bilirubin-related Atazanavir discontinuation within 12 months. Homozygosity for rs887829 T/T was present in 28.1% of Black, 21.4% of Hispanic, and 8.6% of White patients. Among all patients the hazard ratio (HR) for bilirubin-related discontinuation with T/T versus C/C genotype was 7.3 [95% confidence interval (CI): 1.7-31.5; P=0.007]. Among 152 White patients the HR was 14.4 (95% CI: 2.6-78.7; P=0.002), but among 153 Black patients the HR was 0.8 (95% CI: 0.05-12.7; P=0.87). Conclusion Among patients who initiated Atazanavir/ritonavir-containing regimens, UGT1A1 slow metabolizer genotype rs887829 T/T was associated with increased bilirubin-related discontinuation of Atazanavir in White but not in Black patients, this despite T/T genotype being more frequent in Black patients.

  • Race/ethnicity difference in the pharmacogenetics of bilirubin-related Atazanavir discontinuation.
    Pharmacogenetics and genomics, 2018
    Co-Authors: Paul Leger, Lana M. Olson, Sanika Chirwa, Jacinta N Nwogu, Megan Turner, Danielle M Richardson, Paxton Baker, Michael Leonard, Husamettin Erdem, David W. Haas
    Abstract:

    Background Atazanavir causes plasma indirect bilirubin to increase. We evaluated associations between Gilbert's polymorphism and bilirubin-related Atazanavir discontinuation stratified by race/ethnicity. Patients and methods Patients had initiated Atazanavir/ritonavir-containing regimens at an HIV primary care clinic in the southeastern USA, and had at least 12 months of follow-up data. Metabolizer group was defined by UGT1A1 rs887829 C→T. Genome-wide genotype data were used to adjust for genetic ancestry in combined population analyses. Results Among 321 evaluable patients, 15 (4.6%) had bilirubin-related Atazanavir discontinuation within 12 months. Homozygosity for rs887829 T/T was present in 28.1% of Black, 21.4% of Hispanic, and 8.6% of White patients. Among all patients the hazard ratio (HR) for bilirubin-related discontinuation with T/T versus C/C genotype was 7.3 [95% confidence interval (CI): 1.7-31.5; P=0.007]. Among 152 White patients the HR was 14.4 (95% CI: 2.6-78.7; P=0.002), but among 153 Black patients the HR was 0.8 (95% CI: 0.05-12.7; P=0.87). Conclusion Among patients who initiated Atazanavir/ritonavir-containing regimens, UGT1A1 slow metabolizer genotype rs887829 T/T was associated with increased bilirubin-related discontinuation of Atazanavir in White but not in Black patients, this despite T/T genotype being more frequent in Black patients.

  • Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia
    Open forum infectious diseases, 2015
    Co-Authors: Saran Vardhanabhuti, Heather J. Ribaudo, Raphael J. Landovitz, Ighovwerha Ofotokun, Jeffrey L. Lennox, Judith S. Currier, Lana M. Olson, David W. Haas
    Abstract:

    Background.  Some patients are not prescribed Atazanavir because of concern about possible jaundice. Atazanavir-associated hyperbilirubinemia correlates with UGT1A1 rs887829 genotype. We examined bilirubin-related discontinuation of Atazanavir in participants from AIDS Clinical Trials Group Study A5257. Methods.  Discriminatory properties of UGT1A1 T/T genotype for predicting bilirubin-related Atazanavir discontinuation through 96 weeks after antiretroviral initiation were estimated. Results.  Genetic analyses involved 1450 participants, including 481 who initiated randomized Atazanavir/ritonavir. Positive predictive values of rs887829 T/T for bilirubin-related discontinuation of Atazanavir (with 95% confidence intervals [CIs]) were 20% (CI, 9%-36%) in Black, 60% (CI, 32%-84%) in White, and 29% (CI, 8%-58%) in Hispanic participants; negative predictive values were 97% (CI, 93%-99%), 95% (CI, 90%-98%), and 97% (CI, 90%-100%), respectively. Conclusions.  Bilirubin-related discontinuation of Atazanavir was rare in participants not homozygous for rs887829 T/T, regardless of race or ethnicity. We hypothesize that the higher rate of discontinuation among White participants homozygous for rs887829 T/T may reflect differences in physical manifestations of jaundice by race and ethnicity. Selective avoidance of Atazanavir initiation among individuals with T/T genotypes would markedly reduce the likelihood of bilirubin-related discontinuation of Atazanavir while allowing Atazanavir to be prescribed to the majority of individuals. This genetic association will also affect Atazanavir/cobicistat.

  • impact of ugt1a1 gilbert variant on discontinuation of ritonavir boosted Atazanavir in aids clinical trials group study a5202
    The Journal of Infectious Diseases, 2013
    Co-Authors: Heather J. Ribaudo, Gene D Morse, Katie R Mollan, Eric S Daar, Paul E Sax, Margaret A Fischl, Ann C Collier, Camlin Tierney, David W. Haas
    Abstract:

    The UGT1A1*28 variant has been associated with hyperbilirubinemia and Atazanavir discontinuation. Protocol A5202 randomly assigned human immunodeficiency virus type 1 (HIV-1)-infected patients to receive Atazanavir/ritonavir (Atazanavir/r) or efavirenz, with tenofovir/emtricitabine or abacavir/lamivudine. A total of 646 Atazanavir/r recipients were evaluable for UGT1A1. Homozygosity for *28/*28 was present in 8% of whites, 24% of blacks, and 18% of Hispanics and was associated with increased bilirubin concentrations. There was an association between *28/*28 and increased Atazanavir/r discontinuation among Hispanic participants (P = .005) but not among white or black participants (P = .79 and P = .46, respectively). The positive predictive value of 28*/28* for Atazanavir/r discontinuation among Hispanic participants was only 32% (95% confidence interval, 16%-52%).

  • therapy with Atazanavir plus saquinavir in patients failing highly active antiretroviral therapy a randomized comparative pilot trial
    AIDS, 2003
    Co-Authors: David W. Haas, Shannon Schrader, Carlos Zala, Peter J Piliero, H Jaeger, Danilo Nunes, Alexandra Thiry, Steven Schnittman, Michael Sension
    Abstract:

    Objectives: To assess the safety, efficacy of Atazanavir (400 and 600 mg)/saquinavir (1200 mg) once daily versus ritonavir/saquinavir (400 mg/400 mg) twice daily with two nucleoside reverse transcriptase inhibitors (NRTIs) in highly active antiretroviral therapy failure. Design and methods: Randomized, multinational, 48-week, pilot trial with antiretroviral-experienced patients having at least 1000 HIV-1 RNA copies/ml, 100 x 10 6 CD4 cells/l (75 × 10 6 cells/I without AIDS diagnosis) and virological response to a prior regimen. Efficacy was evaluated by HIV-1 RNA and CD4 cell changes from baseline to 48 weeks. Results: Comparable efficacy across groups at 48 weeks: mean HIV-1 RNA decreases, 1.44, 1.19 and 1.66 log 10 copies/ml (P= NS) and comparable virological response (> 1.0 log 10 decrease HIV-1 RNA or HIV-1 RNA < 400 copies/ml) was achieved in 41, 29 and 35% (P = NS); and mean CD4 cell increases, 109, 55 and 149 x 10 6 cells/ I in Atazanavir 400-mg, Atazanavir 600-mg and ritonavir groups, respectively. There were fewer adverse event discontinuations in the Atazanavir groups (9%, 11%) versus the ritonavir group (30%) and Atazanavir lacked adverse effects on lipids. In the Atazanavir 400-mg, Atazanavir 600-mg and ritonavir groups the mean changes from baseline at 48 weeks in fasting low-density lipoprotein (LDL) cholesterol concentrations were -0.6, -6.7 and 23.2%, respectively and in fasting triglyceride concentrations they were -4.8, -27.1 and 93.0%, respectively (P < 0.05, LDL cholesterol; P < 0.001, fasting triglyceride; Atazanavir/saquinavir versus ritonavir/saquinavir). Conclusions: In antiretroviral-experienced patients, once-daily Atazanavir/saquinavir was safe and well tolerated, showing comparable efficacy to twice-daily ritonavir/ saquinavir, both with two NRTIs. Small lipid changes from baseline with Atazanavir/ saquinavir were not clinically significant in comparison with the prompt, marked and sustained changes of a magnitude suggesting clinical relevance achieved in the ritonavir/saquinavir group.

D M Burger - One of the best experts on this subject based on the ideXlab platform.

  • daclatasvir 30 mg day is the correct dose for patients taking Atazanavir cobicistat
    Journal of Antimicrobial Chemotherapy, 2017
    Co-Authors: Elise J Smolders, E P H Colbers, Clara T. M. M. De Kanter, Kirsten Velthovengraafland, Joost P H Drenth, D M Burger
    Abstract:

    BACKGROUND: Atazanavir is boosted with the cytochrome P450 (CYP) 3A4 inhibitor ritonavir. When combined with the CYP3A4 substrate daclatasvir, the daclatasvir dosage should be reduced from 60 to 30 mg once daily. Recently, cobicistat was licensed as a CYP3A booster and used with Atazanavir. OBJECTIVES: To determine whether the fixed-dose combination of Atazanavir/cobicistat has an influence on daclatasvir pharmacokinetics comparable to that of the separate agents Atazanavir and ritonavir. METHODS: A prospective, open-label, two-period, randomized, cross-over trial was performed in 16 healthy subjects (NCT02565888). Treatment consisted of 300/100 mg of Atazanavir/ritonavir plus 30 mg of daclatasvir once daily (reference) and a second period of 300/150 mg of Atazanavir/cobicistat plus 30 mg of daclatasvir once daily (test). A 24 h pharmacokinetic, steady-state curve was recorded for all drugs. Geometric mean ratios (GMRs) with 90% CI were calculated for daclatasvir and Atazanavir AUCτ and Cmax to compare the effect of both treatments (test versus reference). Laboratory safety and adverse events were evaluated throughout the trial. RESULTS: All 16 healthy subjects completed the study. Median (range) age and BMI were 48.5 (21-55) years and 24.5 (19.0-29.2) kg/m(2), respectively. Pharmacokinetic parameters of ritonavir and cobicistat were comparable to those in the literature. The GMRs (90% CI) of daclatasvir AUCτ and Cmax (test versus reference) were 101% (92%-111%) and 97% (89%-106%), respectively. Atazanavir GMRs (90% CI) of AUCτ and Cmax were 82% (75%-79%) and 74% (68%-81%), respectively. No serious adverse events were reported. CONCLUSIONS: Atazanavir/cobicistat and Atazanavir/ritonavir had a similar influence on daclatasvir pharmacokinetics in healthy volunteers. Daclatasvir at 30 mg once daily is the correct dose when combined with Atazanavir/cobicistat.

  • Daclatasvir 30 mg/day is the correct dose for patients taking Atazanavir/cobicistat
    Journal of Antimicrobial Chemotherapy, 2016
    Co-Authors: Elise J Smolders, E P H Colbers, Clara T. M. M. De Kanter, Kirsten Velthoven-graafland, Joost P H Drenth, D M Burger
    Abstract:

    BACKGROUND: Atazanavir is boosted with the cytochrome P450 (CYP) 3A4 inhibitor ritonavir. When combined with the CYP3A4 substrate daclatasvir, the daclatasvir dosage should be reduced from 60 to 30 mg once daily. Recently, cobicistat was licensed as a CYP3A booster and used with Atazanavir. OBJECTIVES: To determine whether the fixed-dose combination of Atazanavir/cobicistat has an influence on daclatasvir pharmacokinetics comparable to that of the separate agents Atazanavir and ritonavir. METHODS: A prospective, open-label, two-period, randomized, cross-over trial was performed in 16 healthy subjects (NCT02565888). Treatment consisted of 300/100 mg of Atazanavir/ritonavir plus 30 mg of daclatasvir once daily (reference) and a second period of 300/150 mg of Atazanavir/cobicistat plus 30 mg of daclatasvir once daily (test). A 24 h pharmacokinetic, steady-state curve was recorded for all drugs. Geometric mean ratios (GMRs) with 90% CI were calculated for daclatasvir and Atazanavir AUCτ and Cmax to compare the effect of both treatments (test versus reference). Laboratory safety and adverse events were evaluated throughout the trial. RESULTS: All 16 healthy subjects completed the study. Median (range) age and BMI were 48.5 (21-55) years and 24.5 (19.0-29.2) kg/m(2), respectively. Pharmacokinetic parameters of ritonavir and cobicistat were comparable to those in the literature. The GMRs (90% CI) of daclatasvir AUCτ and Cmax (test versus reference) were 101% (92%-111%) and 97% (89%-106%), respectively. Atazanavir GMRs (90% CI) of AUCτ and Cmax were 82% (75%-79%) and 74% (68%-81%), respectively. No serious adverse events were reported. CONCLUSIONS: Atazanavir/cobicistat and Atazanavir/ritonavir had a similar influence on daclatasvir pharmacokinetics in healthy volunteers. Daclatasvir at 30 mg once daily is the correct dose when combined with Atazanavir/cobicistat.

  • Therapeutic drug monitoring of the HIV protease inhibitor Atazanavir in clinical practice
    The Journal of antimicrobial chemotherapy, 2007
    Co-Authors: R. M. M. Cleijsen, M. E. Van De Ende, F. P. Kroon, F. Verduyn Lunel, Peter P. Koopmans, L. Gras, F. De Wolf, D M Burger
    Abstract:

    textabstractBackground: Therapeutic drug monitoring (TDM) is being applied for a number of antiretroviral agents. Little is known about the use of TDM for Atazanavir. Methods: This is a retrospective cohort analysis on theuse of TDM of Atazanavir at three clinical sites in The Netherlands. Patients were divided into three groups: (i) all patients with evaluable data of plasma Atazanavir concentrations and its relationship with hyperbilirubinaemia; (ii) patients who started Atazanavir without documented evidence of protease inhibitor (PI) mutations; (iii) patients who started Atazanavir with documented evidence of PI mutations. The genotypic inhibitory quotient (GIQ) was calculated by dividing the mean Atazanavir plasma trough concentration by the number of PI mutations. Results: A total of 108 patients were included; 70 (65.8%) were using Atazanavir/ritonavir (300/100 mg once daily). No significant relationship was observed between Atazanavir plasma trough concentration and antiviral response in patients starting Atazanavir without PI mutations (group 2; n = 82). In contrast, a significant relationship was observed between Atazanavir GIQ and treatment response in patients starting Atazanavir while having PI mutations (group 3; n = 26). The cut-off value for GIQ most predictive of virological failure was 0.23 mg/L/mutation: patients (n = 8) with a GIQ equal to or below this value had 50% virological failure whereas patients (n = 18) with a GIQ above 0.23 mg/L/mutation had only 11% virological failure (χ2: P = 0.030). Atazanavir plasma trough concentrations were significantly related with the occurrence of increased total bilirubin concentrations. Conclusions: TDM of Atazanavir might be beneficial for patients with documented PI resistance or patients with hyperbilirubinaemia. The

Simona Di Giambenedetto - One of the best experts on this subject based on the ideXlab platform.

  • treatment simplification to Atazanavir ritonavir lamivudine versus maintenance of Atazanavir ritonavir two nrtis in virologically suppressed hiv 1 infected patients 48 week results from a randomized trial atlas m
    Journal of Antimicrobial Chemotherapy, 2017
    Co-Authors: Simona Di Giambenedetto, Antonella Castagna, Massimiliano Fabbiani, Eugenia Quiros Roldan, Alessandra Latini, Gabriella Dettorre, Andrea Antinori, Giancarlo Orofino, Daniela Francisci, Pierangelo Chinello
    Abstract:

    Background Combination ART (cART)-related toxicities and costs have prompted the need for treatment simplification. The ATLAS-M trial explored 48 week non-inferior efficacy of simplification to Atazanavir/ritonavir  +  lamivudine versus maintaining three-drug Atazanavir/ritonavir-based cART in virologically suppressed patients. Methods We performed an open-label, multicentre, randomized, non-inferiority study, enrolling HIV-infected adults on Atazanavir/ritonavir + two NRTIs, with stable HIV-RNA 200 cells/mm 3 . Main exclusion criteria were hepatitis B virus coinfection, past virological failure on or resistance to study drugs, recent AIDS and pregnancy. Patients were randomly assigned 1:1 to either switch to 300 mg of Atazanavir/100 mg of ritonavir once daily and 300 mg of lamivudine once daily (Atazanavir/ritonavir + lamivudine arm) or to continue the previous regimen (Atazanavir/ritonavir + two NRTIs arm). The primary study outcome was the maintenance of HIV-RNA <50 copies/mL at week 48 of the ITT-exposed (ITT-e) analysis with switch = failure. The non-inferiority margin was 12%. This study is registered at ClinicalTrials.gov, number NCT01599364. Results Between July 2011 and June 2014, 266 patients were randomized (133 to each arm). After 48 weeks, the primary study outcome was met by 119 of 133 patients (89.5%) in the Atazanavir/ritonavir + lamivudine arm and 106 of 133 patients (79.7%) in the Atazanavir/ritonavir + two NRTIs arm [difference Atazanavir/ritonavir + lamivudine versus Atazanavir/ritonavir + two NRTIs arm: +9.8% (95% CI + 1.2 to + 18.4)], demonstrating non-inferiority and superior efficacy of the Atazanavir/ritonavir + lamivudine arm. Virological failure occurred in two (1.5%) patients in the Atazanavir/ritonavir + lamivudine arm and six (4.5%) patients in the Atazanavir/ritonavir + two NRTIs arm, without resistance selection. A similar proportion of adverse events occurred in both arms. Conclusions Treatment simplification to Atazanavir/ritonavir + lamivudine showed non-inferior efficacy (superiority on post-hoc analysis) and a comparable safety profile over continuing Atazanavir/ritonavir + two NRTIs in virologically suppressed patients.

  • Treatment simplification to Atazanavir/ritonavir + lamivudine versus maintenance of Atazanavir/ritonavir + two NRTIs in virologically suppressed HIV-1-infected patients: 48 week results from a randomized trial (ATLAS-M)
    The Journal of antimicrobial chemotherapy, 2017
    Co-Authors: Simona Di Giambenedetto, Antonella Castagna, Massimiliano Fabbiani, Eugenia Quiros Roldan, Alessandra Latini, Andrea Antinori, Giancarlo Orofino, Daniela Francisci, Gabriella D'ettorre, Pierangelo Chinello
    Abstract:

    Background Combination ART (cART)-related toxicities and costs have prompted the need for treatment simplification. The ATLAS-M trial explored 48 week non-inferior efficacy of simplification to Atazanavir/ritonavir  +  lamivudine versus maintaining three-drug Atazanavir/ritonavir-based cART in virologically suppressed patients. Methods We performed an open-label, multicentre, randomized, non-inferiority study, enrolling HIV-infected adults on Atazanavir/ritonavir + two NRTIs, with stable HIV-RNA 200 cells/mm 3 . Main exclusion criteria were hepatitis B virus coinfection, past virological failure on or resistance to study drugs, recent AIDS and pregnancy. Patients were randomly assigned 1:1 to either switch to 300 mg of Atazanavir/100 mg of ritonavir once daily and 300 mg of lamivudine once daily (Atazanavir/ritonavir + lamivudine arm) or to continue the previous regimen (Atazanavir/ritonavir + two NRTIs arm). The primary study outcome was the maintenance of HIV-RNA

  • Safety and feasibility of treatment simplification to Atazanavir/ritonavir + lamivudine in HIV-infected patients on stable treatment with two nucleos(t)ide reverse transcriptase inhibitors + Atazanavir/ritonavir with virological suppression (Atazanav
    The Journal of antimicrobial chemotherapy, 2013
    Co-Authors: Simona Di Giambenedetto, Massimiliano Fabbiani, Manuela Colafigli, Nicoletta Ciccarelli, Salvatore Farina, Letizia Sidella, Alessandro D’avino, Annalisa Mondi, Antonella Cingolani, Enrica Tamburrini
    Abstract:

    OBJECTIVES To explore 48 week safety and efficacy of treatment simplification to Atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression on a stable Atazanavir/ritonavir-based standard triple regimen. METHODS This was a single-arm pilot study, enrolling 40 patients on Atazanavir/ritonavir + two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), without previous treatment failure, with HIV-RNA 3 months and CD4 >200 cells/mm(3). At baseline, patients were switched to 300/100 mg of Atazanavir/ritonavir + 300 mg of lamivudine once daily. Laboratory parameters, Atazanavir plasma levels, self-reported adherence, quality of life, neurocognitive performance, bone composition and body fat distribution were monitored. Virological failure was defined as HIV-RNA >50 copies/mL on two consecutive determinations or a single level >1000 copies/mL. RESULTS After 48 weeks, 4/40 (10%) regimen discontinuations occurred: 1 death (brain haemorrhage), 1 study withdrawal (inadequate Atazanavir plasma levels), 1 re-induction with two NRTIs due to pregnancy and 1 virological failure without development of resistance. Seven moderate to severe adverse events were recorded (including four renal colics, possibly treatment-related) in six patients. At week 48, increases in total (mean change +17 mg/dL, P = 0.001), high-density lipoprotein (+6 mg/dL, P 

Richard Bertz - One of the best experts on this subject based on the ideXlab platform.

  • Atazanavir pharmacokinetics, efficacy and safety in pregnancy: a systematic review.
    Antiviral therapy, 2012
    Co-Authors: Timothy Eley, Richard Bertz, Helene Hardy, David M. Burger
    Abstract:

    BACKGROUND: For some antiretroviral therapies, drug concentrations are reduced during pregnancy, potentially compromising effective virological suppression. METHODS: Data on Atazanavir boosted with ritonavir in pregnancy are reviewed. RESULTS: With standard Atazanavir/ritonavir 300/100 mg once-daily dosing: Atazanavir area-under-the-concentration-time curves were reduced during pregnancy in most studies, but overall interpretation differed according to the data used for comparison; Atazanavir concentration 24 h post-dose was maintained >150 ng/ml in 97.6% of women; no instance of mother-to-child transmission occurred in treatment-adherent mothers; and infant hyperbilirubinaemia was not elevated beyond levels expected in the neonatal period. CONCLUSIONS: With concurrent medications that reduce Atazanavir drug concentrations, optimal therapy during pregnancy may require once-daily Atazanavir/ritonavir 400/100 mg; however, using this dose during the third trimester doubled maternal grade 3-4 hyperbilirubinaemia rates.

  • Effect of Low‐Dose Omeprazole (20 mg Daily) on the Pharmacokinetics of Multiple‐Dose Atazanavir With Ritonavir in Healthy Subjects
    Journal of clinical pharmacology, 2010
    Co-Authors: Li Zhu, Anna Persson, Lisa Mahnke, Timothy Eley, Sangeeta Agarwala, Jeffrey Dragone, Richard Bertz
    Abstract:

    Atazanavir, a potent protease inhibitor of human immunodeficiency virus (HIV), exhibits pH-dependent solubility. Previous studies have indicated that coadministration with omeprazole 40 mg once daily significantly decreased Atazanavir exposure by approximately 75%. Concomitant use of omeprazole and Atazanavir is currently not recommended. This study investigated a clinically effective, low dose of omeprazole (20 mg daily) on Atazanavir pharmacokinetics in 56 healthy volunteers given Atazanavir/ ritonavir 300/100 and 400/100 mg once daily. All Atazanavir/ritonavir plus omeprazole combinations resulted in Atazanavir area under the concentration―time curve (AUC) and trough concentrations (C min ) comparable to or exceeding those observed with Atazanavir 400 mg without omeprazole. Compared with Atazanavir/ritonavir 300/100 mg without omeprazole, Atazanavir/ritonavir 300/100 mg plus omeprazole reduced Atazanavir AUC and C min by 42% and 46%, respectively. Increasing the Atazanavir/ritonavir dose to 400/100 mg attenuated the effect of omeprazole, resulting in approximately 30 % lower Atazanavir C min , with all individual C min values exceeded by greater than 10-fold the population mean protein binding―adjusted EC 90 against wild-type HIV. The effect of omeprazole on Atazanavir/ritonavir 400/100 mg was similar whether given 1 hour prior to atozanavir/ ritonavir or separated by 12 hours. No unexpected adverse events were noted. This study found that omeprazole 20 mg once daily has significantly less profound effects on Atazanavir pharmacokinetics than previously observed with omeprazole 40 mg.

  • Pharmacokinetics and safety of twice-daily Atazanavir 300 mg and raltegravir 400 mg in healthy individuals.
    Antiviral therapy, 2010
    Co-Authors: Li Zhu, Anna Persson, Joan R. Butterton, Michele Stonier, Wendy Comisar, Deborah Panebianco, Sheila Breidinger, Jenny Zhang, Richard Bertz
    Abstract:

    Background Atazanavir plus raltegravir 300/400 mg twice daily is being explored as a ritonavir- and nucleoside-sparing treatment strategy. The pharmacokinetics and safety of this combination in healthy individuals were evaluated. Methods A total of 22 healthy individuals received raltegravir 400 mg on days 1-5, Atazanavir 300 mg on days 6-12 and Atazanavir plus raltegravir 300/400 mg on days 13-26, twice daily with a light meal. Serial blood samples were collected 12 h after the morning dose on days 5, 12 and 26; safety assessments, clinical laboratory data and serial electrocardiograms (ECGs) at 0, 2 and 6 h were obtained. Results Raltegravir coadministration reduced Atazanavir geometric mean maximum plasma concentration (C(max)), area under the plasma concentration-time curve from 0 to 12 h post-dose (AUC(0-12)) and trough plasma concentration (C(min)) by 11%, 17% and 29%, respectively, compared with Atazanavir alone. Geometric mean Atazanavir C(min) was 817 ng/ml (range 250-1,550) with raltegravir coadministration. Atazanavir increased raltegravir geometric mean C(max), AUC(0-12) and C(min) by 39%, 54% and 48%, respectively. All adverse events were of mild or moderate intensity. Hyperbilirubinaemia and ECG PR increases with Atazanavir were similar to those of Atazanavir/ritonavir once daily. No corrected QT prolongations were noted. Mean QRS increase from baseline was 11.0 ms (range 2-25) after receiving Atazanavir for 7 days; no further QRS increase was noted and no QRS interval was >120 ms with raltegravir coadministration. No ECG changes were observed with raltegravir alone. Conclusions Coadministration of Atazanavir and raltegravir 300/400 mg twice daily decreased Atazanavir AUC(0-12) and C(min) relative to Atazanavir alone, and increased AUC(0-12) of raltegravir relative to raltegravir alone. Atazanavir and raltegravir alone and coadministered appeared safe and well-tolerated.

  • effect of concomitantly administered rifampin on the pharmacokinetics and safety of Atazanavir administered twice daily
    Antimicrobial Agents and Chemotherapy, 2007
    Co-Authors: Edward P. Acosta, Sangeeta Agarwala, Richard Bertz, Michelle A. Kendall, John G. Gerber, Susan L. Koletar, Andrew R. Zolopa, Michael Child, Beverly Alstonsmith, Lara Hosey
    Abstract:

    The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor Atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg Atazanavir every 12 h without rifampin (period 1), 300 mg Atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg Atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C12 h) was 811 ng/ml (range, 363 to 2,484 ng/ml) for Atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg Atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C12 h values for Atazanavir were 44 ng/ml (range, <25 to187 ng/ml) and 113 ng/ml (range, 39 to 260 ng/ml), respectively, well below historic seronegative data for once-daily treatment with 400 mg Atazanavir without ritonavir. Although safe and generally well tolerated, 300 mg or 400 mg Atazanavir administered every 12 h did not maintain adequate plasma exposure when coadministered with rifampin. Tuberculosis is a leading cause of mortality in human immunodeficiency virus (HIV)-infected individuals and accounts for about 13% of all AIDS deaths worldwide (19). Rifampin is a cornerstone of effective antituberculosis therapy. Unfortunately, potent induction of hepatic cytochrome P450 3A (CYP3A) expression by rifampin markedly lowers plasma concentrations of HIV protease inhibitors (13). The antituberculosis drug rifabutin induces CYP3A activity less than rifampin and may therefore be coadministered with many HIV protease inhibitors (13), but rifabutin is not available in most resourcelimited countries. Although rifampin may be coadministered with the nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine, there are many situations in which efavirenz and nevirapine may not be appropriate. Additional safe and effective strategies are urgently needed to treat coinfection with HIV and Mycobacterium tuberculosis. Atazanavir is a widely prescribed HIV protease inhibitor. It undergoes metabolism by hepatic CYP3A, which generates two metabolites that lack antiviral activity (3). Approved dosages are 400 mg once daily when prescribed without ritonavir and 300 mg once daily when boosted with 100 mg ritonavir once daily (3). In antiretroviral therapy-nao ¨ve individuals, Atazanavir-containing regimens have activity that is broadly

  • Effect of Concomitantly Administered Rifampin on the Pharmacokinetics and Safety of Atazanavir Administered Twice Daily
    Antimicrobial agents and chemotherapy, 2007
    Co-Authors: Edward P. Acosta, Sangeeta Agarwala, Richard Bertz, Michelle A. Kendall, John G. Gerber, Beverly Alston-smith, Susan L. Koletar, Andrew R. Zolopa, Michael Child, Lara Hosey
    Abstract:

    The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor Atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg Atazanavir every 12 h without rifampin (period 1), 300 mg Atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg Atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C12 h) was 811 ng/ml (range, 363 to 2,484 ng/ml) for Atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg Atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C12 h values for Atazanavir were 44 ng/ml (range,

Jeanmichel Molina - One of the best experts on this subject based on the ideXlab platform.

  • high levels of Atazanavir and darunavir in urine and crystalluria in asymptomatic patients
    Journal of Antimicrobial Chemotherapy, 2013
    Co-Authors: Victoire De Lastours, Jeanmichel Molina, Michel Daudon, Erika Ferrari Rafael De Silva, Raphael Porcher, Benedicte Loze, Helene Sauvageon
    Abstract:

    Objectives: Atazanavir has been associated with kidney stones and renal failure. We measured urine and plasma concentrations of recent protease inhibitors (PIs) and searched for PI crystals in the urine of asymptomatic patients. Methods: A cross-sectional analysis of HIV-infected patients taking ritonavir-boosted Atazanavir 300 mg/day (ATV300/r), unboosted Atazanavir 400 mg/day (ATV400), ritonavir-boosted darunavir at either 800 mg/day (DRV800/r) or 1200 mg/day (DRV1200/r) or ritonavir-boosted lopinavir 800 mg/day was performed. Plasma and urine were collected and PI levels measured using HPLC. Crystals were detected and identified in urine using polarized microscopy. Results: PI levels were measured in 266 patients, 142 of whom were assessed for urinary crystals. Their mean age was 46 years. The mean duration of HIV infection was 10.5 years and the mean duration of the current PIcontaining regimen was 22.5 months. The mean CD4 cell count was 494 cells/mm 3 ; 74% showed controlled HIV replication. Median urinary PI levels were 22.3, 14.3, 26.9 and 29.7 mg/L for ATV300/r, ATV400, DRV800/r and DRV1200/r, respectively, significantly higher than plasma levels, which were all ,5 mg/L (P,0.001). In contrast, median urinary lopinavir concentrrations did not significantly differ from plasma concentrations (4.2 and 6.4 mg/L, respectively; P ¼0.7) and were significantly lower than those of other PIs (P,0.001). Atazanavir crystals were found in 7/78 patients receiving ATV300/r (8.9%; 95% CI¼2.6%‐15.2%) and darunavir crystals were found in 4/51 patients receiving darunavir (7.8%; 95% CI¼0.4%‐15.2%). Longer exposure to Atazanavir was the only risk factor associated with the presence of Atazanavir crystalluria (P ¼0.04). Conclusions: Unlike lopinavir, Atazanavir and darunavir reached high concentrations in urine. Urinary crystals were found in a few patients receiving ritonavir-boosted Atazanavir or darunavir and may favour nephrolithiasis.

  • once daily Atazanavir ritonavir compared with twice daily lopinavir ritonavir each in combination with tenofovir and emtricitabine for management of antiretroviral naive hiv 1 infected patients 96 week efficacy and safety results of the castle study
    Journal of Acquired Immune Deficiency Syndromes, 2010
    Co-Authors: Jeanmichel Molina, Graeme Moyle, Jaime Andradevillanueva, Juan Echevarria, Ploenchan Chetchotisakd, Jorge Corral, Neal David, Marco Mancini, Lisa Percival, Rong Yang
    Abstract:

    Background: Once-daily Atazanavir/ritonavir demonstrated similar antiviral efficacy to twice-daily lopinavir/ritonavir over 48 weeks, with less gastrointestinal disturbance and a better lipid profile, in treatment-naive patients. Methods: International, multicenter, open-label, 96-week noninferiority randomized trial of Atazanavir/ritonavir 300/100 mg once daily vs lopinavir/ritonavir 400/100 mg twice daily, each in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily, in antiretroviral-naive, HIV-1-infected patients. The primary end point was the proportion of patients with HIV RNA <50 copies/mL at 48 weeks. Results through 96 weeks are reported. Results: Of 883 patients enrolled, 440 were randomized to Atazanavir/ritonavir and 443 to lopinavir/ritonavir. At week 96, more patients receiving Atazanavir/ritonavir achieved HIV RNA <50 copies/mL (74% vs 68%, P < 0.05) in the intent-to-treat analysis. On both regimens, 7% of subjects were virologic failures by 96 weeks. Bilirubin-associated disorders were greater in patients taking Atazanavir/ritonavir. Treatment-related gastrointestinal adverse events were greater in patients taking lopinavir/ritonavir. Mean changes from baseline in fasting total cholesterol, non-high-density lipoprotein cholesterol, and triglycerides at week 96 were significantly higher with lopinavir/ritonavir (P < 0.0001). Conclusions: Noninferiority of Atazanavir/ritonavir to lopinavir/ ritonavir was confirmed at 96 weeks. Atazanavir/ritonavir had a better lipid profile and fewer gastrointestinal adverse events than lopinavir/ritonavir.

  • once daily Atazanavir ritonavir versus twice daily lopinavir ritonavir each in combination with tenofovir and emtricitabine for management of antiretroviral naive hiv 1 infected patients 48 week efficacy and safety results of the castle study
    The Lancet, 2008
    Co-Authors: Jeanmichel Molina, Graeme Moyle, Jaime Andradevillanueva, Juan Echevarria, Ploenchan Chetchotisakd, Jorge Corral, Neal David, Marco Mancini, Lisa Percival, Rong Yang
    Abstract:

    Summary Background Atazanavir/ritonavir is as effective as lopinavir/ritonavir, with a more favourable lipid profile and less gastrointestinal toxicity, in treatment-experienced HIV-1-infected patients. We compared these two combinations directly in treatment-naive patients. Methods In this open-label, international non-inferiority study, 883 antiretroviral-naive, HIV-1-infected patients were randomly assigned to receive Atazanavir/ritonavir 300/100 mg once daily (n=440) or lopinavir/ritonavir 400/100 mg twice daily (n=443), in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily. Randomisation was done with a computer-generated centralised randomisation schedule and was stratified by baseline levels of HIV RNA (viral load) and geographic region. The primary endpoint was the proportion of patients with viral load less than 50 copies per mL at week 48. The main efficacy analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00272779. Findings At week 48, 343 (78%) of 440 patients receiving Atazanavir/ritonavir and 338 (76%) of 443 patients receiving lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL (difference 1·7%, 95% CI −3·8 to 7·1). Mean increases from baseline in CD4 cell count were similar (203 cells per μL in the Atazanavir/ritonavir group vs 219 cells per μL in the lopinavir/ritonavir group). 25 (6%) patients in the Atazanavir/ritonavir group and 26 (6%) in the lopinavir/ritonavir group were virological failures by week 48. Only two patients, both in the Atazanavir/ritonavir group, had non-polymorphic protease inhibitor resistance mutations emerge on treatment, which conferred phenotypic resistance to Atazanavir in one patient. Serious adverse events were noted in 51 (12%) of 441 patients in the Atazanavir/ritonavir group and in 42 (10%) of 437 patients in the lopinavir/ritonavir group. Fewer patients in the Atazanavir/ritonavir group than in the lopinavir/ritonavir group experienced grade 2–4 treatment-related diarrhoea (10 [2%] vs 50 [11%]) and nausea (17 [4%] vs 33 [8%]). Grade 2–4 jaundice was seen in 16 (4%) of 441 patients in the Atazanavir/ritonavir group versus none of 437 patients in the lopinavir/ritonavir group; grade 3–4 increases in total bilirubin were seen in 146 (34%) of 435 patients on Atazanavir/ritonavir and in one ( Interpretation In treatment-naive patients, Atazanavir/ritonavir once-daily demonstrated similar antiviral efficacy to lopinavir/ritonavir twice-daily, with less gastrointestinal toxicity but with a higher rate of hyperbilirubinaemia. Funding Bristol-Myers Squibb.