-
Pharmacotherapy Dec 2004Atazanavir is the first once-daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy,... (Review)
Review
Atazanavir is the first once-daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy, as part of a highly active antiretroviral therapy (HAART) regimen. In addition to being the most potent protease inhibitor in vitro, atazanavir has a distinct cross-resistance profile that does not confer resistance to other protease inhibitors. However, resistance to other protease inhibitors often confers clinically relevant resistance to atazanavir. Currently, atazanavir is not a preferred protease inhibitor for initial HAART regimens. In treatment-naive patients, atazanavir can be given as 400 mg/day. However, atazanavir should be pharmacologically boosted with ritonavir in treatment-experienced patients or when coadministered with either tenofovir or efavirenz. Patients who receive atazanavir experience similar rates of adverse events compared with patients receiving comparator regimens. An exception is an increased risk of asymptomatic hyperbilirubinemia, which is due to competitive inhibition of uridine diphosphate-glucuronosyltransferase 1A1. Although hyperbilirubinemia is a common adverse drug reaction of atazanavir therapy (22-47%), fewer than 2% of patients discontinue atazanavir therapy because of this adverse effect. Common adverse effects reported with atazanavir include infection, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash. Of significance, fewer abnormalities have been observed in plasma lipid profiles in patients treated with atazanavir compared with other protease inhibitor-containing regimens. As with other protease inhibitors, atazanavir is also a substrate and moderate inhibitor of the cytochrome P450 (CYP) system, in particular CYP3A4 and CYP2C9. Clinically significant drug interactions include (but are not limited to) antacids, proton pump inhibitors, histamine type 2 receptor antagonists, tenofovir, diltiazem, irinotecan, simvastatin, lovastatin, St. John's wort, and warfarin. We conclude that atazanavir is a distinctively characteristic protease inhibitor owing to its in vitro potency, once-daily dosing, distinct initial resistance pattern, and infrequent association with metabolic abnormalities.
Topics: Anti-HIV Agents; Atazanavir Sulfate; Drug Interactions; Drug Resistance, Viral; HIV Infections; Humans; Oligopeptides; Pyridines
PubMed: 15585441
DOI: 10.1592/phco.24.17.1732.52347 -
European Journal of Pharmacology Jun 2018Atazanavir is an antiretroviral medication used to treat and prevent HIV/AIDS, but its effects on cardiac fibrosis are unknown. The aim of this study was to determine...
Atazanavir is an antiretroviral medication used to treat and prevent HIV/AIDS, but its effects on cardiac fibrosis are unknown. The aim of this study was to determine the effects of atazanavir on myocardial infarction (MI)-induced cardiac fibrosis in rats and used a TLR 9 antagonist, hydroxychloroquine (HCQ) to elucidate the potential mechanism in vitro. The results indicated that atazanavir significantly attenuated CoCl-induced neonatal rat cardiac fibroblast (rCFs) proliferation in a concentration-dependent manner. Treatment of rCFs with atazanavir 1-10 µM blocked CoCl-induced nuclear factor kappaB phosphorylation (p-NF-κB), p-IκBα and high-mobility group box 1 (HMGB1) expression. Treatment of rCFs with atazanavir 3 µM blocked HMGB1 downstream, p-NF-κB by blocking HMGB1 binds to toll-like receptor 9 (TLR 9). Intragastric administration of atazanavir sulfate 30 mg/k ameliorated changes in the left ventricular systolic pressure (LVSP), + dp/dtmax, and - dp/dtmax after 4 weeks. This was associated with attenuation of α-SMA, HMGB1, p-NF-κB, TLR 9, collagen I, collagen III expression and hydroxyproline (Hyp) content in ischemic myocardial tissue. Additionally, continuous intragastric administration of atazanavir for 28 days attenuated cardiac remodeling. These data suggested that the protective effect of atazanavir is likely due to blocking of myocardial inflammatory cascades through an HMGB1/TLR 9 signaling pathway.
Topics: Administration, Oral; Animals; Atazanavir Sulfate; Cell Line; Cell Proliferation; Collagen; Fibroblasts; Fibrosis; Gene Expression Regulation; Heart; Hypertrophy; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Time Factors
PubMed: 29605419
DOI: 10.1016/j.ejphar.2018.03.041 -
Acta Pharmaceutica (Zagreb, Croatia) Mar 2020A UPLC-MS method for the estimation of atazanavir sulfate was developed using the "analytical quality by design" approach. The critical chromatographic quality...
A UPLC-MS method for the estimation of atazanavir sulfate was developed using the "analytical quality by design" approach. The critical chromatographic quality attributes identified were retention time, theoretical plates and peak tailing. The critical method parameters established were percent of organic modifier, flow rate and injection volume. Optimization performed using Box-Behnken Design (BBD) established 10 % organic modifier, 0.4 mL min-1 flow rate and 6-µL injection volume as the optimum method conditions. Atazanavir sulfate eluted at 5.19 min without any interference. Method validation followed international guidelines. The method has proven linearity in the range of 10-90 µg mL-1. Recovery was between 100.2-101.0 % and precision within the accepted limits (RSD 0.2-0.7 %). LOD and LOQ were 2.68 and 8.14 µg mL-1, resp. Stress testing stability studies showed atazanavir sulfate to degrade under acidic and basic conditions. The suggested technique is simple, rapid and sustainable. It is, therefore, suggested for routine analysis of atazanavir sulfate.
Topics: Atazanavir Sulfate; Chromatography, High Pressure Liquid; Drug Stability; HIV Protease Inhibitors; Hydrogen-Ion Concentration; Mass Spectrometry
PubMed: 31677371
DOI: 10.2478/acph-2020-0008 -
Clinical Pharmacology and Therapeutics Apr 2016The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and... (Review)
Review
The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).
Topics: Atazanavir Sulfate; Genetic Predisposition to Disease; Genotype; Glucuronosyltransferase; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Jaundice; Liver; Pharmacogenetics; Phenotype; Risk Assessment; Risk Factors
PubMed: 26417955
DOI: 10.1002/cpt.269 -
Current Opinion in Infectious Diseases Feb 2018To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. (Review)
Review
PURPOSE OF REVIEW
To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations.
RECENT FINDINGS
For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted with ritonavir (/r)], darunavir/r has been shown to be associated with increased CVD risk. The effect is cumulative with longer exposure increasing risk and an effect size comparable to what has been observed for previously developed protease inhibitors. Biological mechanisms may be overlapping and include perturbed lipid metabolism and accumulation of cholesterol derivatives within macrophages. Conversely, atazanavir/r has not been shown to be associated with CVD, possibly because of its ability to increase cardioprotective bilirubin levels.
SUMMARY
Evidence linking protease inhibitors to CVD is based on observational studies only, whereas plausible biological explanations are well established and derived from randomized trials and controlled experiments. Given the possible association with clinical disease, a conservative approach to apply the data in daily practise is proposed which is focused on individualization of care based on underlying risk of CVD.
Topics: Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Cardiovascular Diseases; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Risk Assessment; Ritonavir
PubMed: 29232276
DOI: 10.1097/QCO.0000000000000425 -
Frontiers in Immunology 2023Inflammation-induced free radical release is important in the pathogenesis of several diseases, including atherosclerosis and sepsis. Heme oxygenase (HO) breaks down...
OBJECTIVE
Inflammation-induced free radical release is important in the pathogenesis of several diseases, including atherosclerosis and sepsis. Heme oxygenase (HO) breaks down heme into carbon monoxide, iron, and biliverdin. Biliverdin IXα is directly converted to bilirubin by biliverdin reductase. Unconjugated bilirubin is a powerful antioxidant, and elevated levels have beneficial effects in preclinical models and human cardiovascular disease. However, its impact during acute inflammation in humans is unknown. In the present study, we investigated the impact of atazanavir-induced (unconjugated) hyperbilirubinemia on antioxidant capacity, inflammation, and vascular dysfunction in human experimental endotoxemia.
APPROACH AND RESULTS
Following double-blinded four-day treatment with atazanavir 2dd300 mg (or placebo), twenty healthy male volunteers received 2 ng/kg lipopolysaccharide intravenously. Blood was drawn to determine the bilirubin levels, antioxidant capacity, and cytokine response. It was demonstrated that following atazanavir treatment, total bilirubin concentrations increased to maximum values of 4.67 (95%CI 3.91-5.59) compared to 0.82 (95%CI 0.64-1.07) mg/dL in the control group (p<0.01). Furthermore, the anti-oxidant capacity, as measured by the ferric-reducing ability of plasma (FRAP), was significantly increased with 36% in hyperbilirubinemia subjects (p<0.0001), and FRAP concentrations correlated strongly to bilirubin concentrations (R2 = 0.77, p<0.001). Hyperbilirubinemia attenuated the release of interleukin-10 from 377 (95%CI 233-609) to 219 (95%CI 152-318) pg/mL (p=0.01), whereas the release of pro-inflammatory cytokines remained unaltered. , in the absence of hyperbilirubinemia, atazanavir did not influence lipopolysaccharide-induced cytokine release in a whole blood assay. Vascular function was assessed using forearm venous occlusion plethysmography after intra-arterial infusion of acetylcholine and nitroglycerin. Hyperbilirubinemia completely prevented the LPS-associated blunted vascular response to acetylcholine and nitroglycerin.
CONCLUSIONS
Atazanavir-induced hyperbilirubinemia increases antioxidant capacity, attenuates interleukin-10 release, and prevents vascular hyporesponsiveness during human systemic inflammation elicited by experimental endotoxemia.
CLINICAL TRIAL REGISTRATION
http://clinicaltrials.gov, identifier NCT00916448.
Topics: Humans; Male; Atazanavir Sulfate; Interleukin-10; Nitroglycerin; Endotoxemia; Lipopolysaccharides; Acetylcholine; Antioxidants; Biliverdine; Hyperbilirubinemia; Bilirubin
PubMed: 37261364
DOI: 10.3389/fimmu.2023.1176775 -
Journal of Acquired Immune Deficiency... Mar 2022This study evaluated atazanavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples.
BACKGROUND
This study evaluated atazanavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples.
SETTING
A nonrandomized, open-label, parallel-group, multicenter prospective study of atazanavir and cobicistat pharmacokinetics in pregnant women with HIV and their children.
METHODS
Intensive steady-state 24-hour pharmacokinetic profiles were performed after administration of 300 mg of atazanavir and 150 mg of cobicistat orally in fixed-dose combination once daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Atazanavir and cobicistat were measured in plasma by validated high-performance liquid chromatography-ultraviolet and liquid chromatography-tandem mass spectrometry assays, respectively. A 2-tailed Wilcoxon signed-rank test (α = 0.10) was used for paired within-participant comparisons.
RESULTS
A total of 11 pregnant women enrolled in the study. Compared with paired postpartum data, atazanavir AUC0-24 was 26% lower in the second trimester [n = 5, P = 0.1875, geometric mean of ratio (GMR) = 0.739, 90% CI: 0.527 to 1.035] and 54% lower in the third trimester (n = 6, GMR = 0.459, P = 0.1563, 90% CI: 0.190 to 1.109), whereas cobicistat AUC0-24 was 35% lower in the second trimester (n = 5, P = 0.0625, GMR = 0.650, 90% CI: 0.493 to 0.858) and 52% lower in the third trimester (n = 7, P = 0.0156, GMR = 0.480, 90% CI: 0.299 to 0.772). The median (interquartile range) 24-hour atazanavir trough concentration was 0.21 μg/mL (0.16-0.28) in the second trimester, 0.21 μg/mL (0.11-0.56) in the third trimester, and 0.61 μg/mL (0.42-1.03) in postpartum. Placental transfer of atazanavir and cobicistat was limited.
CONCLUSIONS
Standard atazanavir/cobicistat dosing during pregnancy results in lower exposure which may increase the risk of virologic failure and perinatal transmission.
Topics: Anti-HIV Agents; Atazanavir Sulfate; Child; Cobicistat; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infectious Disease Transmission, Vertical; Placenta; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies
PubMed: 34732682
DOI: 10.1097/QAI.0000000000002856 -
Prescrire International Sep 2014
Topics: Atazanavir Sulfate; HIV Protease Inhibitors; Humans; Oligopeptides; Pyridines; Risk Assessment; Risk Factors; Urolithiasis
PubMed: 25325124
DOI: No ID Found -
International Journal of STD & AIDS Sep 2007
Topics: Adult; Atazanavir Sulfate; Female; HIV Infections; HIV Protease Inhibitors; Humans; Menorrhagia; Oligopeptides; Pyridines
PubMed: 17785018
DOI: 10.1258/095646207781568637 -
The Journal of Antimicrobial... Nov 2017Atazanavir (300 mg) boosted by ritonavir (100 mg) is the preferred third drug in pregnancy. However, there is still discordance on atazanavir dose increase during... (Observational Study)
Observational Study
BACKGROUND
Atazanavir (300 mg) boosted by ritonavir (100 mg) is the preferred third drug in pregnancy. However, there is still discordance on atazanavir dose increase during the third trimester.
OBJECTIVES
To evaluate plasma and intracellular atazanavir and ritonavir concentrations in HIV-infected women during pregnancy and after delivery.
METHODS
This was an observational study. HIV-infected pregnant patients treated with atazanavir/ritonavir plus either tenofovir/emtricitabine or abacavir/lamivudine had been prospectively enrolled after having signed a written informed consent form. Plasma and intracellular atazanavir and ritonavir Ctrough (24 ± 3 h after drug intake) were measured at each visit during the first, second and third trimesters and post-partum using validated HPLC-MS and HPLC-photodiode array methods (with direct evaluation of cellular volume). Data are described as median (IQR) and compared through non-parametric tests.
RESULTS
Twenty-five patients were enrolled; at baseline, the median age was 32 years (27-35). All patients had plasma HIV RNA <50 copies/mL; the median CD4+ count was 736 cells/mm3 (542-779). Atazanavir plasma concentrations were 441 ng/mL (261-1557), 710 ng/mL (338-1085), 556 ng/mL (334-1022) and 837 ng/mL (608-1757) during the first, second and third trimesters and post-partum, respectively; intracellular concentrations were 743 ng/mL (610-1928), 808 ng/mL (569-1620), 756 ng/mL (384-1074) and 706 ng/mL (467-2688), respectively. Atazanavir intracellular/plasma ratios were 1.32 (0.98-2.77), 1.34 (1.13-1.88), 1.38 (0.61-2.63) and 1.07 (0.56-2.69), respectively. Atazanavir intracellular concentrations and intracellular/plasma ratios showed non-significant changes over time (P > 0.05).
CONCLUSIONS
This is the first demonstration that intracellular atazanavir exposure remains unchanged during pregnancy supporting the standard 300/100 mg atazanavir/ritonavir dosing throughout pregnancy.
Topics: Adult; Atazanavir Sulfate; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant, Newborn; Leukocytes, Mononuclear; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimesters; Prospective Studies; RNA, Viral; Ritonavir; Tenofovir; Viral Load
PubMed: 28961777
DOI: 10.1093/jac/dkx274