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BMC Infectious Diseases Apr 2017Atazanavir/ritonavir and darunavir/ritonavir are common protease inhibitor-based regimens for treating patients with HIV. Studies comparing these drugs in clinical... (Comparative Study)
Comparative Study
BACKGROUND
Atazanavir/ritonavir and darunavir/ritonavir are common protease inhibitor-based regimens for treating patients with HIV. Studies comparing these drugs in clinical practice are lacking.
METHODS
We conducted a retrospective cohort study of antiretroviral naïve participants in the Canadian Observational Cohort (CANOC) collaboration initiating atazanavir/ritonavir- or darunavir/ritonavir-based treatment. We used separate Fine and Gray competing risk regression models to compare times to regimen failure (composite of virologic failure or discontinuation for any reason). Additional endpoints included virologic failure, discontinuation due to virologic failure, discontinuation for other reasons, and virologic suppression.
RESULTS
We studied 222 patients treated with darunavir/ritonavir and 1791 patients treated with atazanavir/ritonavir. Following multivariable adjustment, there was no difference between darunavir/ritonavir and atazanavir-ritonavir in the risk of regimen failure (adjusted hazard ratio 0.76, 95% CI 0.56 to 1.03) Darunavir/ritonavir-treated patients were at lower risk of virologic failure relative to atazanavir/ritonavir treated patients (aHR 0.50, 95% CI 0.28 to 0.91), findings driven largely by high rates of virologic failure among atazanavir/ritonavir-treated patients in the province of British Columbia. Of 108 discontinuations due to virologic failure, all occurred in patients starting atazanavir/ritonavir. There was no difference between regimens in time to discontinuation for reasons other than virologic failure (aHR 0.93; 95% CI 0.65 to 1.33) or virologic suppression (aHR 0.99, 95% CI 0.82 to 1.21).
CONCLUSIONS
The risk of regimen failure was similar between patients treated with darunavir/ritonavir and atazanavir/ritonavir. Although darunavir/ritonavir was associated with a lower risk of virologic failure relative to atazanavir/ritonavir, this difference varied substantially by Canadian province and likely reflects regional variation in prescribing practices and patient characteristics.
Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; British Columbia; Canada; Cohort Studies; Darunavir; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Retrospective Studies; Ritonavir
PubMed: 28399819
DOI: 10.1186/s12879-017-2379-8 -
Journal of Pharmaceutical Analysis Apr 2017A stability-indicating reverse phase-high performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of atazanavir sulfate in...
A stability-indicating reverse phase-high performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of atazanavir sulfate in tablet dosage forms using C column Phenomenix (250 mm×4.6 mm, 5 μm) with a mobile phase consisting of 900 mL of HPLC grade methanol and 100 mL of water of HPLC grade. The pH was adjusted to 3.55 with acetic acid. The mobile phase was sonicated for 10 min and filtered through a 0.45 μm membrane filter at a flow rate of 0.5 mL/min. The detection was carried out at 249 nm and retention time of atazanavir sulfate was found to be 8.323 min. Linearity was observed from 10 to 90 μg/mL (coefficient of determination was 0.999) with equation, =23.427+37.732. Atazanavir sulfate was subjected to stress conditions including acidic, alkaline, oxidation, photolysis and thermal degradation, and the results showed that it was more sensitive towards acidic degradation. The method was validated as per ICH guidelines.
PubMed: 29404029
DOI: 10.1016/j.jpha.2013.12.002 -
PloS One 2020Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used...
HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells.
OBJECTIVES
Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs' effects on inflammation, senescence and also insulin resistance.
METHODS
We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects.
RESULTS
Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant. From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NFκB activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable.
CONCLUSION
USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance.
Topics: Anti-HIV Agents; Atazanavir Sulfate; Cells, Cultured; Comorbidity; Coronary Vessels; Endothelial Cells; Female; HIV Infections; Heterocyclic Compounds, 3-Ring; Humans; Insulin Resistance; Male; Maraviroc; NF-kappa B; Oxazines; Piperazines; Pyridones; Ritonavir; Signal Transduction; Sirtuin 1; Ubiquitin Thiolesterase
PubMed: 31971958
DOI: 10.1371/journal.pone.0226924 -
Clinical Infectious Diseases : An... May 2024Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of...
BACKGROUND
Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin.
METHODS
DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with human immunodeficiency virus (HIV) on atazanavir/ritonavir-based antiretroviral therapy (ART) in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg twice a day (BID) with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data were interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L.
RESULTS
We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, whereas 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported a serious adverse event (SAE) or experienced rebound viraemia.
CONCLUSIONS
Twice daily atazanavir/ritonavir during rifampicin co-administration was well tolerated and achieved plasma concentrations above the target.
CLINICAL TRIALS REGISTRATION
NCT04121195. Registered on 09 October 2019, https://clinicaltrials.gov/ct2/show/NCT04121195.
Topics: Humans; Atazanavir Sulfate; Rifampin; Ritonavir; Male; Female; Adult; HIV Infections; Drug Interactions; Middle Aged; HIV Protease Inhibitors; Uganda; Anti-HIV Agents; Drug Therapy, Combination; Drug Administration Schedule
PubMed: 37982585
DOI: 10.1093/cid/ciad700 -
AIDS (London, England) May 2016To evaluate the safety of in-utero exposure to atazanavir and neurodevelopment in perinatally HIV-exposed but uninfected (PHEU) infants. (Comparative Study)
Comparative Study
OBJECTIVE
To evaluate the safety of in-utero exposure to atazanavir and neurodevelopment in perinatally HIV-exposed but uninfected (PHEU) infants.
DESIGN
Prospective cohort study of mother-PHEU infant pairs in the Surveillance Monitoring for ART Toxicities protocol of the Pediatric HIV/AIDS Cohort Study.
METHODS
Pregnant women living with HIV who initiated an antiretroviral regimen during pregnancy were followed from the date of antiretroviral initiation. Women were classified according to whether the antiretroviral regimen contained atazanavir and the trimester of antiretroviral initiation. Neurodevelopment at 9-15 months was evaluated using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). We estimated mean differences for the five Bayley-III domains for atazanavir-containing regimens versus all other regimens. Models included baseline covariates and adjustment for failure to complete the Bayley-III using inverse probability weighting.
RESULTS
PHEU infants were exposed in utero to atazanavir-containing (n = 167) and nonatazanavir-containing (n = 750) antiretroviral regimens. The adjusted mean differences (95% confidence interval) in Bayley-III domain scores for initiating an atazanavir-containing regimen in the first trimester were: cognitive, -1.5 (-6.2, 3.2); language, -3.3 (-7.6, 1.0); motor, -2.9 (-7.7, 1.9); social-emotional, 0.1 (-6.2, 6.4); and adaptive behavior, -0.1 (-4.3, 4.0). The mean differences for the second or third trimester were: cognitive, 0.4 (-3.2, 4.0); language, -3.4 (-6.2, -0.5); motor, 0.3 (-2.9, 3.4); social-emotional, -5.9 (-9.4, -2.3); and adaptive behavior, -2.5 (-5.9, 0.8).
CONCLUSION
In-utero exposure to atazanavir-containing regimens compared with non-atazanavir-containing regimens may adversely affect language and social-emotional development in PHEU infants during the first year of life, but the absolute difference is small.
Topics: Adult; Atazanavir Sulfate; Female; Fetal Development; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Infant, Newborn; Male; Nervous System; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Prospective Studies; Young Adult
PubMed: 26867136
DOI: 10.1097/QAD.0000000000001052 -
British Journal of Clinical Pharmacology Jul 2011S/GSK1349572 is an unboosted, once daily, next generation integrase inhibitor with potent activity, low pharmacokinetic (PK) variability and a novel resistance profile.... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
S/GSK1349572 is an unboosted, once daily, next generation integrase inhibitor with potent activity, low pharmacokinetic (PK) variability and a novel resistance profile. As the primary route of metabolism is via glucuronidation, the effects of atazanavir (ATV, a UGT1A1 inhibitor) and atazanavir/ritonavir (ATV/RTV) on S/GSK1349572 PK were evaluated.
METHODS
A randomized, open label, two period, crossover study was conducted in healthy adult subjects. Twenty-four subjects received S/GSK1349572 30 mg every 24 h for 5 days. Subjects then were administered S/GSK1349572 30 mg every 24 h in combination with either ATV/RTV 300/100 mg every 24 h (n= 12) or ATV 400 mg every 24 h (n= 12) for 14 days. Serial PK samples and safety assessments were obtained throughout the study.
RESULTS
The combination of S/GSK1349572 with ATV/RTV or ATV was generally well tolerated. All adverse events were mild or moderate, and no subject withdrew because of an adverse event. The AE of highest frequency was ocular icterus, observed only during combination of S/GSK1349572 and ATV or ATV/RTV. Co-administration with ATV/RTV resulted in increased plasma S/GSK1349572 area under the concentration-time curve during a dosing interval (AUC(0,τ)), observed maximal concentration (C(max) ), and concentration at the end of dosing interval at steady state (C(τ) ) by 62%, 34% and 121%, respectively. Co-administration with ATV resulted in increased plasma S/GSK1349572 AUC(0,τ), C(max) , and C(τ) by 91%, 50% and 180%, respectively.
CONCLUSIONS
Co-administration of ATV/RTV and ATV was generally well tolerated and produced a modest, non-clinically significant increase in S/GSK1349572 exposure. No dose adjustment for S/GSK1349572 is necessary when co-administered with ATV and ATV/RTV.
Topics: Adolescent; Adult; Area Under Curve; Atazanavir Sulfate; Cross-Over Studies; Drug Administration Schedule; Drug Combinations; Drug Interactions; Female; Glucuronosyltransferase; HIV Integrase Inhibitors; HIV Protease Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Linear Models; Male; Middle Aged; Oligopeptides; Oxazines; Piperazines; Pyridines; Pyridones; Ritonavir; Young Adult
PubMed: 21342217
DOI: 10.1111/j.1365-2125.2011.03947.x -
Scientific Reports Dec 2020To increase the success in Covid 19 treatment, many drug suggestions are presented, and some clinical studies are shared in the literature. There have been some attempts... (Review)
Review
To increase the success in Covid 19 treatment, many drug suggestions are presented, and some clinical studies are shared in the literature. There have been some attempts to use some of these drugs in combination. However, using more than one drug together may cause serious side effects on patients. Therefore, detecting drug-drug interactions of the drugs used will be of great importance in the treatment of Covid 19. In this study, the interactions of 8 drugs used for Covid 19 treatment with 645 different drugs and possible side effects estimates have been produced using Graph Convolutional Networks. As a result of the experiments, it has been found that the hematopoietic system and the cardiovascular system are exposed to more side effects than other organs. Among the focused drugs, Heparin and Atazanavir appear to cause more adverse reactions than other drugs. In addition, as it is known that some of these 8 drugs are used together in Covid-19 treatment, the side effects caused by using these drugs together are shared. With the experimental results obtained, it is aimed to facilitate the selection of the drugs and increase the success of Covid 19 treatment according to the targeted patient.
Topics: Atazanavir Sulfate; COVID-19; Drug Interactions; Heparin; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33299085
DOI: 10.1038/s41598-020-78697-1 -
Pharmacology Research & Perspectives Apr 2023Previous use of a mechanistic static model to accurately quantify the increased rosuvastatin exposure due to drug-drug interaction (DDI) with coadministered atazanavir...
Mechanistic in vitro studies indicate that the clinical drug-drug interactions between protease inhibitors and rosuvastatin are driven by inhibition of intestinal BCRP and hepatic OATP1B1 with minimal contribution from OATP1B3, NTCP and OAT3.
Previous use of a mechanistic static model to accurately quantify the increased rosuvastatin exposure due to drug-drug interaction (DDI) with coadministered atazanavir underpredicted the magnitude of area under the plasma concentration-time curve ratio (AUCR) based on inhibition of breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1. To reconcile the disconnect between predicted and clinical AUCR, atazanavir and other protease inhibitors (darunavir, lopinavir and ritonavir) were evaluated as inhibitors of BCRP, OATP1B1, OATP1B3, sodium taurocholate cotransporting polypeptide (NTCP) and organic anion transporter (OAT) 3. None of the drugs inhibited OAT3, nor did darunavir and ritonavir inhibit OATP1B3 or NTCP. All drugs inhibited BCRP-mediated estrone 3-sulfate transport or OATP1B1-mediated estradiol 17β-D-glucuronide transport with the same rank order of inhibitory potency (lopinavir>ritonavir>atazanavir>>darunavir) and mean IC values ranging from 15.5 ± 2.80 μM to 143 ± 14.7 μM or 0.220 ± 0.0655 μM to 9.53 ± 2.50 μM, respectively. Atazanavir and lopinavir also inhibited OATP1B3- or NTCP-mediated transport with a mean IC of 1.86 ± 0.500 μM or 65.6 ± 10.7 μM and 5.04 ± 0.0950 μM or 20.3 ± 2.13 μM, respectively. Following integration of a combined hepatic transport component into the previous mechanistic static model using the in vitro inhibitory kinetic parameters determined above for atazanavir, the newly predicted rosuvastatin AUCR reconciled with the clinically observed AUCR confirming additional minor involvement of OATP1B3 and NTCP inhibition in its DDI. The predictions for the other protease inhibitors confirmed inhibition of intestinal BCRP and hepatic OATP1B1 as the principal pathways involved in their clinical DDI with rosuvastatin.
Topics: Rosuvastatin Calcium; ATP Binding Cassette Transporter, Subfamily G, Member 2; Protease Inhibitors; Lopinavir; Ritonavir; Darunavir; Atazanavir Sulfate; Neoplasm Proteins; Drug Interactions
PubMed: 36811234
DOI: 10.1002/prp2.1060 -
Scientia Pharmaceutica 2016A capillary gas chromatography method with a short run time, using a flame ionization detector, has been developed for the quantitative determination of trace level...
A capillary gas chromatography method with a short run time, using a flame ionization detector, has been developed for the quantitative determination of trace level analysis of mesityl oxide and diacetone alcohol in the atazanavir sulfate drug substance. The chromatographic method was achieved on a fused silica capillary column coated with 5% diphenyl and 95% dimethyl polysiloxane stationary phase (Rtx-5, 30 m x 0.53 mm x 5.0 µm). The run time was 20 min employing programmed temperature with a split mode (1:5) and was validated for specificity, sensitivity, precision, linearity, and accuracy. The detection and quantitation limits obtained for mesityl oxide and diacetone alcohol were 5 µg/g and 10 µg/g, respectively, for both of the analytes. The method was found to be linear in the range between 10 µg/g and 150 µg/g with a correlation coefficient greater than 0.999, and the average recoveries obtained in atazanavir sulfate were between 102.0% and 103.7%, respectively, for mesityl oxide and diacetone alcohol. The developed method was found to be robust and rugged. The detailed experimental results are discussed in this research paper.
PubMed: 27222607
DOI: 10.3797/scipharm.1507-05 -
International Journal of Molecular... Oct 2022The human immunodeficiency virus type 1 (HIV-1) has continued to be a global concern. With the new HIV incidence, the emergence of multi-drug resistance and the untoward...
The human immunodeficiency virus type 1 (HIV-1) has continued to be a global concern. With the new HIV incidence, the emergence of multi-drug resistance and the untoward side effects of currently used anti-HIV drugs, there is an urgent need to discover more efficient anti-HIV drugs. Modern computational tools have played vital roles in facilitating the drug discovery process. This research focuses on a pharmacophore-based similarity search to screen 111,566,735 unique compounds in the PubChem database to discover novel HIV-1 protease inhibitors (PIs). We used an in silico approach involving a 3D-similarity search, physicochemical and ADMET evaluations, HIV protease-inhibitor prediction (IC/percent inhibition), rigid receptor-molecular docking studies, binding free energy calculations and molecular dynamics (MD) simulations. The 10 FDA-approved HIV PIs (saquinavir, lopinavir, ritonavir, amprenavir, fosamprenavir, atazanavir, nelfinavir, darunavir, tipranavir and indinavir) were used as reference. The in silico analysis revealed that fourteen out of the twenty-eight selected optimized hit molecules were within the acceptable range of all the parameters investigated. The hit molecules demonstrated significant binding affinity to the HIV protease (PR) when compared to the reference drugs. The important amino acid residues involved in hydrogen bonding and п-п stacked interactions include ASP25, GLY27, ASP29, ASP30 and ILE50. These interactions help to stabilize the optimized hit molecules in the active binding site of the HIV-1 PR (PDB ID: 2Q5K). HPS/002 and HPS/004 have been found to be most promising in terms of IC/percent inhibition (90.15%) of HIV-1 PR, in addition to their drug metabolism and safety profile. These hit candidates should be investigated further as possible HIV-1 PIs with improved efficacy and low toxicity through in vitro experiments and clinical trial investigations.
Topics: Humans; HIV Protease Inhibitors; HIV Protease; Darunavir; Indinavir; Nelfinavir; Ritonavir; Saquinavir; Lopinavir; Atazanavir Sulfate; Molecular Docking Simulation; HIV-1; Anti-HIV Agents; Amino Acids
PubMed: 36293006
DOI: 10.3390/ijms232012149