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Drug Metabolism and Disposition: the... Mar 2016The aim of this study was to explore the mechanisms governing the intra- to extracellular unbound concentration ratio (Kpu,u) for the HIV protease inhibitor atazanavir...
The aim of this study was to explore the mechanisms governing the intra- to extracellular unbound concentration ratio (Kpu,u) for the HIV protease inhibitor atazanavir (ATV) in rat hepatocytes. We had previously proposed a new method to determine Kpu,u by using the unbound Km values from metabolism studies with suspended rat hepatocytes and rat liver microsomes. Following that method, we determined that the value of ATV Kpu,u was 0.32, indicating that ATV hepatocellular clearance is uptake rate-limited. This hypothesis was supported by the linear correlation between Kpu,u and active uptake clearance (P = 0.04; R(2)=0.82) in the presence of increasing concentrations of the uptake transport inhibitor losartan. Moreover, in contrast to an expected increase of Kpu,u upon inhibition of ATV metabolism, a decrease of Kpu,u was observed, suggesting an increased impact of sinusoidal efflux. In summary, involvement of active uptake transport does not guarantee high intracellular accumulation; however, it has a key role in regulating intracellular drug concentrations and drug metabolism. These findings will help improve future in vitro-to-in vivo extrapolations and likewise physiologically based pharmacokinetic models.
Topics: Animals; Atazanavir Sulfate; Biological Transport, Active; HIV Protease Inhibitors; Hepatocytes; Losartan; Male; Microsomes, Liver; Rats; Rats, Wistar
PubMed: 26712820
DOI: 10.1124/dmd.115.068114 -
Annales de Biologie Clinique Aug 2019
Topics: Adult; Atazanavir Sulfate; Darunavir; Drug Administration Schedule; Drug Substitution; HIV Infections; Hepatitis C; Humans; Inactivation, Metabolic; Late Onset Disorders; Liver; Male; Time Factors; Urolithiasis
PubMed: 31418708
DOI: 10.1684/abc.2019.1471 -
The New England Journal of Medicine Sep 2022Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as... (Comparative Study)
Comparative Study
BACKGROUND
Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited.
METHODS
We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results.
RESULTS
Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar.
CONCLUSIONS
Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Cobicistat; Cohort Studies; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Infant, Newborn; Oxazines; Piperazines; Pregnancy; Premature Birth; Pyridones; Quinolones; Raltegravir Potassium; Rilpivirine; Ritonavir; United States
PubMed: 36053505
DOI: 10.1056/NEJMoa2200600 -
International Journal of STD & AIDS May 2014We present a case of a 41-year-old man complaining of chest pain, which he directly attributed to his antiretrovirals, specifically atazanavir and ritonavir. The chest...
We present a case of a 41-year-old man complaining of chest pain, which he directly attributed to his antiretrovirals, specifically atazanavir and ritonavir. The chest pain resolved on stopping the treatment, and recurred when atazanavir was restarted, again resolving on discontinuation. Cardiovascular risk factors are an important consideration with any antiretroviral therapy but particularly with protease inhibitors. The association between atazanavir and cardiac arrhythmias has been reported elsewhere including the British National Formulary, and it may be good practice to perform electrocardiogram assessments in patients commencing and using atazanavir-based regimens.
Topics: Adult; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Chest Pain; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Male; Oligopeptides; Pyridines; Treatment Outcome
PubMed: 24108452
DOI: 10.1177/0956462413506890 -
Basic & Clinical Pharmacology &... Mar 2021Molidustat is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl-hydroxylase enhancing the erythropoietin (EPO) response to HIF; it is in clinical development...
Molidustat is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl-hydroxylase enhancing the erythropoietin (EPO) response to HIF; it is in clinical development for the treatment of anaemia related to chronic kidney disease. The predominant role of glucuronidation for molidustat clearance (formation of N-glucuronide metabolite M1) and subsequent renal excretion was confirmed in a human mass balance study, with about 85% of the drug being excreted as M1 in urine. The inhibitory effects of 176 drugs and xenobiotics from various compound classes on the UGT-mediated glucuronidation of molidustat in human liver microsomes (HLMs) were investigated. Based on preclinical findings, glucuronidation of molidustat was predominantly mediated by the 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT1A1. Therefore, atazanavir, which is a potent inhibitor of UGT1A1, was chosen for the evaluation of pharmacokinetics and EPO release following a single oral dose of 25 mg molidustat. Molidustat exposure increased about twofold upon coadministration with atazanavir when considering area under plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (C ). Baseline-corrected increase of EPO was 14% and 34% for C and AUC (calculated over 24 hours), respectively. Coadministration of molidustat and atazanavir was well tolerated.
Topics: Adult; Atazanavir Sulfate; Drug Interactions; Erythropoietin; Glucuronides; Glucuronosyltransferase; Humans; Male; Middle Aged; Pyrazoles; Triazoles; Young Adult
PubMed: 33232579
DOI: 10.1111/bcpt.13538 -
Clinical Pharmacology in Drug... Mar 2017Hyperbilirubinemia is a common finding in individuals with a history of substance abuse. Although this may indicate a serious disorder of liver function, this is not...
Hyperbilirubinemia is a common finding in individuals with a history of substance abuse. Although this may indicate a serious disorder of liver function, this is not always the case. An understanding of bilirubin formation, metabolism, and transport can provide a helpful approach to dealing with these patients. This is typified by studies of patients treated with the antiretroviral drug atazanavir. Atazanavir has been associated with hyperbilirubinemia in as many as one-third of individuals for whom it has been prescribed, evoking concerns of hepatotoxicity. The studies in this report were designed to determine mechanisms by which this occurs. The data show that this drug inhibits the enzyme UDP-glucuronosyl transferase-1A1, responsible for conjugating bilirubin with glucuronic acid. This conjugation step is required for bilirubin excretion into bile, and when it is inhibited, bilirubin refluxes from the liver into the circulation, causing unconjugated hyperbilirubinemia. Other parameters of bilirubin formation, binding to albumin in the circulation, uptake into hepatocytes, and intracellular protein binding in hepatocytes were unaffected by atazanavir. The effect of atazanavir on serum bilirubin levels is reversible, consistent with lack of structural damage to the liver.
Topics: Animals; Atazanavir Sulfate; Bilirubin; Cells, Cultured; Female; Glucuronosyltransferase; Glutathione Transferase; HIV Protease Inhibitors; Hepatocytes; Humans; Hyperbilirubinemia; Male; Rats, Wistar; Ritonavir; Substance-Related Disorders
PubMed: 28263463
DOI: 10.1002/cpdd.314 -
International Journal of STD & AIDS Nov 2016Porphyrias are a group of metabolic disorders that are relatively uncommon and underdiagnosed. Although the association between HIV infection and antiretrovirals with...
Porphyrias are a group of metabolic disorders that are relatively uncommon and underdiagnosed. Although the association between HIV infection and antiretrovirals with porphyria cutanea tarda is well established, there are fewer data linking HIV and the acute hepatic porphyrias. We report the first case of acute intermittent porphyria precipitated by the drugs atazanavir and ritonavir, presenting with unexplained abdominal pain.
Topics: Abdominal Pain; Atazanavir Sulfate; Female; HIV Infections; Humans; Middle Aged; Porphyria, Acute Intermittent; Protease Inhibitors; Ritonavir; Treatment Outcome
PubMed: 26872826
DOI: 10.1177/0956462416633981 -
Prescrire International 2011
Topics: Atazanavir Sulfate; Child; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir
PubMed: 21751749
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Sep 2020Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012....
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.
Topics: Animals; Antiviral Agents; Atazanavir Sulfate; Betacoronavirus; COVID-19; Cell Death; Chlorocebus aethiops; Coronavirus 3C Proteases; Coronavirus Infections; Cysteine Endopeptidases; Cytokines; Drug Therapy, Combination; Humans; Inflammation; Lopinavir; Molecular Docking Simulation; Monocytes; Pandemics; Pneumonia, Viral; Protease Inhibitors; Ritonavir; SARS-CoV-2; Vero Cells; Viral Nonstructural Proteins; Virus Replication; COVID-19 Drug Treatment
PubMed: 32759267
DOI: 10.1128/AAC.00825-20 -
The Journal of Antimicrobial... Jul 2018To investigate the long-term safety and efficacy of a treatment switch to dual ART with atazanavir/ritonavir + lamivudine versus continuing a standard regimen with... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To investigate the long-term safety and efficacy of a treatment switch to dual ART with atazanavir/ritonavir + lamivudine versus continuing a standard regimen with atazanavir/ritonavir + 2NRTI in virologically suppressed patients.
METHODS
ATLAS-M is a 96 week open-label, randomized, non-inferiority (margin -12%) trial enrolling HIV-infected adults on atazanavir/ritonavir + 2NRTI, with stable HIV-RNA <50 copies/mL and CD4 counts >200 cells/mm3. At baseline, patients were randomized 1:1 to switch to atazanavir/ritonavir + lamivudine or to continue the previous regimen. Here, we report the 96 week efficacy and safety data. The study was registered with ClinicalTrials.gov, number NCT01599364.
RESULTS
Overall, 266 subjects were enrolled (133 in each arm). At 96 weeks, in the ITT population, patients free of treatment failure totalled 103 (77.4%) with atazanavir/ritonavir + lamivudine and 87 (65.4%) with triple therapy (difference +12.0%, 95% CI +1.2/+22.8, P = 0.030), demonstrating the superiority of dual therapy. Two (1.5%) and 9 (6.8%) virological failures occurred in the dual-therapy arm and the triple-therapy arm, respectively, without development of resistance to any study drug. Clinical adverse events occurred at similar rates in both arms. A higher frequency of grade 3-4 hyperbilirubinemia (66.9% versus 50.4%, P = 0.006) and hypertriglyceridaemia (6.8% versus 1.5%, P = 0.031) occurred with dual therapy, although this never led to treatment discontinuation. A significant improvement in renal function and lumbar spine bone mineral density occurred in the dual-therapy arm. The evolution of CD4, HIV-DNA levels and neurocognitive performance was similar in both arms.
CONCLUSIONS
In this randomized study, a treatment switch to atazanavir/ritonavir + lamivudine was superior over the continuation of atazanavir/ritonavir + 2NRTI in virologically suppressed patients, with a sustained benefit in terms of improved renal function and bone mineral density.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; RNA, Viral; Ritonavir; Treatment Failure; Treatment Outcome; Viral Load
PubMed: 29668978
DOI: 10.1093/jac/dky123