Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atazanavir is the most recently introduced protease inhibitor for the suppression of the anti-human immunodeficiency virus. A sensitive and selective reversed-phase liquid chromatographic assay for this drug in human plasma has been developed and validated. Atazanavir was isolated from a 500 microL plasma sample using liquid-liquid extraction with dichloromethane. After evaporation and reconstitution of the extract the sample was analysed using liquid chromatography and ultraviolet detection at 280 nm. In the evaluated concentration range (44-4395 ng/mL atazanavir), intra-day precisions were < or =7% and inter-day precisions were < or =14%. Accuracies between 96 and 106% were found. The lower limit of quantification was 44 ng/mL with an intra-day precision of 7%, an inter-day precision of 14% and an accuracy of 87%. There was no interference from 32 tested potentially co-administrated drugs and metabolites. The usefulness of the assay was demonstrated for samples obtained from an HIV-infected patient treated with atazanavir.
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PMID:Liquid chromatographic assay for the protease inhibitor atazanavir in plasma. 1595 63

Drug resistance testing is increasingly used to guide treatment decisions in patients infected with HIV-1. A number of rules-based algorithms have been designed to predict drug resistance profiles based on the HIV-1 genotypic data. Drug-resistance mutations in 206 viral samples from protease inhibitor (PI)-experienced subjects with HIV-1 infection were assessed, and the level of susceptibility of the samples predicted using seven unique algorithms. kappa scores were used to compare agreement of results obtained using each of the predictive algorithms with the phenotypic assay results. Good overall agreement between the different algorithms and the phenotypic results was observed. Good or excellent agreement was observed between the results obtained by the predictive algorithms and the phenotypic assay results for ritonavir, indinavir, saquinavir, and nelfinavir. For amprenavir and lopinavir, there were marked differences between the different algorithms, with poor agreement (kappa < 0.40) obtained with four of the seven algorithms for amprenavir. For lopinavir, poor agreement was obtained with three of seven algorithms using the 2.5-fold biological cut-off and four of seven with the clinical cut-off of 10. Atazanavir susceptibility was evaluated for concordance among six algorithms, with a range of 23-50% of the samples maintaining susceptibility. Although this cohort of patients included many who were highly antiretroviral experienced, predictive algorithms demonstrated good agreement with phenotype for several Pls. For those where discordance among algorithms existed, further improvement will likely occur as drug resistance pathways for the more recently approved PIs are elucidated.
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PMID:Comparison of HIV type 1 protease inhibitor susceptibility results in viral samples analyzed by phenotypic drug resistance assays and by six resistance algorithms: an analysis of a subpopulation of the CHORUS cohort. 1613 8

The efficacy of HIV-1 protease inhibitors (PIs) as part of highly active antiretroviral therapy is now well established and has provided benefits to many patients with HIV infection. Atazanavir is a new azapeptide PI compound that was recently approved in the US and Europe. Atazanavir is recommended in combination with other antiretroviral agents for the treatment of HIV-1 infection. Atazanavir is rapidly absorbed and administration of a single dose of atazanavir with a light meal resulted in a 70% increase in area under the plasma concentration-time curve (AUC); therefore atazanavir should be taken with food. Atazanavir is 86% bound to human serum protein independently of concentration. Concentration in body fluids appeared to be lower than plasma concentration. Like other PIs, atazanavir is extensively metabolised by hepatic cytochrome P450 (CYP) 3A isoenzymes. The mean terminal elimination half-life in healthy volunteers was approximately 7 hours at steady state following administration of atazanavir 400 mg daily with a light meal. When atazanavir 300 mg was coadministered with ritonavir 100 mg on a once-daily dosage regimen, atazanavir AUC from 0 to 24 hours and minimum plasma concentration were increased by 3- to 4-fold and approximately 10-fold, respectively, compared with atazanavir 300 mg alone. Therefore, ritonavir boosted atazanavir regimen (ritonavir 100 mg and atazanavir 300 mg once daily) is increasingly favoured in some patients. Efavirenz, a potent CYP3A inducer, decreased atazanavir concentrations by 75% and, unexpectedly, tenofovir, a nucleotide reverse transcriptase inhibitor, decreased atazanavir concentrations by 25%. Average predose concentrations in HIV-infected patients who received atazanavir 400mg once daily were 273 ng/mL, which was believed to be several-fold higher than protein-binding corrected 50% inhibitory concentration of wild-type viruses. In HIV-infected patients who received once-daily ritonavir (100mg) boosted atazanavir (300 mg), mean (+/-SD) trough concentration was 862 (+/-838) ng/mL. Several clinical trials showed the efficacy of atazanavir 400 mg once daily with a nucleoside analogue backbone in antiretroviral-naive patients. The atazanavir 300/ritonavir 100 mg once-daily combination coadministered with other antiretrovirals showed the efficacy of this strategy in patients receiving efavirenz or in moderately antiretroviral-experienced HIV-infected patients. Recommended once-daily doses of atazanavir taken with food are either 400 mg or 300 mg in combination with low dose ritonavir (100 mg) in moderately antiretroviral-experienced patients. Major advantages of atazanavir to date are its simplicity of administration (once-daily administration) and its less undesirable effect on the lipid profiles in patients.
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PMID:Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. 1617 17

Atazanavir (Reyataz) is a novel protease inhibitor (PI) approved for use in combination with other antiretroviral drugs for the treatment of HIV infection. In antiretroviral therapy (ART)-experienced patients the drug is administered with low-dose ritonavir (i.e. boosted). In the US, unboosted atazanavir is also approved for use in ART-naive patients. In adult patients with HIV infection, atazanavir-containing highly active antiretroviral therapy (HAART) regimens provided marked improvements in virological and immunological markers and was generally well tolerated. Furthermore, recommended atazanavir regimens were no less effective than, and generally as well tolerated as, other HAART regimens in these patients, including regimens containing co-formulated lopinavir/ritonavir. Atazanavir may have an advantage over other PIs because of its favourable effect on lipid profiles, once-daily dosing, low capsule burden and, in patients with low prior PI exposure, a favourable resistance profile. Given these advantages and taking into consideration between-country differences in the approved indications, atazanavir is a valuable option as the PI component of HAART for the management of HIV infection in adult ART-naive patients, particularly where metabolic complications are a concern, and as a first- or second-line PI in combination with low-dose ritonavir in adult ART-experienced patients.
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PMID:Atazanavir: a review of its use in the management of HIV infection. 1626 2

The clinical use of HIV protease inhibitors (PIs) is associated with the development of peripheral insulin resistance. The incidence and degree of impaired glucose tolerance observed in treated patients vary considerably between drugs, however. To compare the ability of HIV PIs to alter peripheral glucose disposal acutely in a genetically identical model system at therapeutically relevant drug levels, healthy lean male rats previously naive to PI exposure were given ritonavir, amprenavir, lopinavir/ritonavir (4:1), or atazanavir by continuous intravenous infusion to achieve steady state drug levels of 10 or 25 muM rapidly. Under euglycemic hyperinsulinemic clamp conditions, a dose-dependent reduction in the peripheral glucose disposal rate (Rd) was observed with all the PIs except atazanavir. The rank order of sensitivity was ritonavir, lopinavir, and then amprenavir. Changes in skeletal muscle and heart 2-deoxyglucose (2-DOG) uptake correlated with reductions in Rd. All 3 of these PIs also produced significant reductions in 2-DOG uptake into primary rat adipocytes in vitro. Atazanavir had no effect on glucose uptake in vitro or in vivo. The in vivo potency of PIs to impair peripheral glucose disposal acutely correlates with the degree of insulin resistance observed in HIV-infected patients receiving these drugs. Preclinical testing of novel candidate PIs in a rodent model system may be useful in identifying the future risk of altering glucose homeostasis.
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PMID:Direct comparison of the acute in vivo effects of HIV protease inhibitors on peripheral glucose disposal. 1628 Jun 93

More and more HIV-infected patients are treated for viral hepatitis, increasing interactions. HEPATITIS C: The concomitant use of didanosine and ribavirin increases the risk of mitochondrial toxicity, responsible for pancreatitis and/or lactic acidosis. Lactic acidosis is characterized by a high mortality rate. Thus, didanosine, but also stavudine, should not be co-administered with ribavirin. Cases of hepatic decompensation have been reported in cirrhotics concomitantly receiving ribavirin and didanosine. Thus, this co-admininistration should be contraindicated in patients with advanced liver fibrosis. Anemia is a frequent side effect of ribavirin. In patients with zidovudine-related anemia, this drug should be discontinued before prescribing ribavirin. Erythropoietin may help to improve the haemoglobin level. HEPATITIS B: Adefovir significantly decreases the plasma levels of saquinavir. Pancreatitis may occur with the co-administration of didanosine and tenofovir. Thus this co-administration should be avoided. Atazanavir concentrations are decreased when tenofovir is co-administered. Thus, atazanavir should be boosted with ritonavir, when combined with tenofovir. Atazanavir increases the concentrations of tenofovir, with the potential risk of increasing the adverse events of tenofovir, including renal disorders. Tenofovir area under the curve is increased if lopinavir-ritonavir are co-administered. The main interactions, with a fatal risk, are observed with didanosine, when co-administered with ribavirin (hepatitis C) or with tenofovir (hepatitis B). Anemia is frequent, but usually moderate, when zidovudine is co-administered with ribavirin. Other interactions are usually easy to manage.
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PMID:Antiviral hepatitis and antiretroviral drug interactions. 1636 Feb 31

The pharmacokinetics and short-term safety of atazanavir 150 and 200 mg, when coadministered with saquinavir/ritonavir 1600/100 mg once daily, were evaluated. On day 1, atazanavir 150 mg once daily, was added to saquinavir/ritonavir regimens and sampling was performed to evaluate saquinavir, ritonavir, and atazanavir pharmacokinetics (day 11). Atazanavir was increased to 200 mg and pharmacokinetic assessment repeated (day 30). Geometric mean ratios (GMR) and 95% confidence intervals (CI) were used to compare saquinavir, ritonavir, and atazanavir pharmacokinetic parameters in the present study and for 14 of the subjects treated with saquinavir/ritonavir 1600/100 mg once daily without and with atazanavir 300 mg who participated in a previous trial. Geometric mean (GM) saquinavir AUC0-24, Ctrough, and Cmax were 30,589 and 32,312 ng . h/ml, 166 and 182 ng/ml, and 4267 and 4261 ng/ml when coadministered with atazanavir 150 and 200 mg (n = 18). On days 11 and 30, saquinavir and atazanavir Ctrough remained >100 ng/ml in 13/18, 14/18, 18/18, and 17/18 patients. Among the above mentioned 14 subjects, significant increases in saquinavir Ctrough (87%, 92%, 99%), Cmax (40%, 55%, 44%), and AUC0-24 (51%, 60%, 63%) were observed with atazanavir 300, 150, and 200 mg. Ritonavir AUC0-24 and Cmax were significantly increased with the addition of atazanavir 300 mg only. Atazanavir enhances saquinavir and ritonavir by a mechanism that requires elucidation. While saquinavir enhancement was apparently independent of atazanavir dose, atazanavir 300 mg produced an increase in ritonavir Cmax, which is not observed with lower atazanavir doses. Atazanavir-related hyperbilirubinemia was dose dependent. However, higher saquinavir and atazanavir exposure may be required to suppress HIV-resistant strain replication.
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PMID:Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV Type 1-infected individuals administered different atazanavir doses. 1691 Aug 30

Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h(-1) (CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.
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PMID:Population pharmacokinetics of atazanavir in patients with human immunodeficiency virus infection. 1694 65

ASPIRE I and II were prospective, 3-way sequential crossover studies in healthy volunteers to compare the safety and pharmacokinetics of saquinavir/ritonavir (SQV/RTV) with saquinavir/atazanavir (SQV/ATV) administered either once daily (QD, ASPIRE I) or twice daily (BID, ASPIRE II). Treatments were separated by 10 days, and pharmacokinetic analyses were performed on days 11, 32, and 53. SQV pharmacokinetics were significantly higher when dosed with RTV compared to ATV (P < .05 for all comparisons). ATV pharmacokinetics were similar within treatment arms. ATV Cmin increased approximately 60%, and Cmax decreased approximately 35% with BID dosing compared with QD dosing. Women had higher exposure for all 3 protease inhibitors (PIs) compared with men after adjusting for weight. Adverse effects were primarily gastrointestinal-related with SQV/RTV and hyperbilirubinemia with SQV/ATV. Although SQV plasma concentrations were higher when coadministered with RTV, a combination of SQV/ATV administered BID may be a viable alternative in HIV-infected, PI-naive subjects intolerant to RTV.
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PMID:Pharmacokinetics of saquinavir with atazanavir or low-dose ritonavir administered once daily (ASPIRE I) or twice daily (ASPIRE II) in seronegative volunteers. 1724 71

HIV protease inhibitors (PIs) have been associated with the serious Metabolic Syndrome, which is the major risk factor of atherosclerotic cardiovascular disease. Atherosclerosis is widely considered to be a chronic inflammatory disease. Macrophages are the most prominent cell type present in atherosclerotic lesions and play essential roles in both early lesion development and late lesion complications. We previously reported that HIV PIs induced accumulation of intracellular free cholesterol and lipids, decreased endoplasmic reticulum (ER) calcium stores, activated the unfolded protein response (UPR), significantly increased apoptosis, and promoted foam cell formation in macrophages. HIV PI-induced ER stress and subsequent activation of the UPR, represents an important cell signaling mechanism of HIV PI-induced metabolic syndromes. Here we show that all HIV PIs, except amprenavir, increased expression of the major mediators of inflammatory response, TNF-alpha and IL-6, to varying degrees. Furthermore, we show that the RNA-binding protein, HuR, plays an important role in HIV PI-induced expression of TNF-alpha and IL-6. Atazanavir increased the cytoplasmic levels of HuR and enhanced the binding of HuR to 3'-UTR of TNF-alpha and IL-6. Down regulation of HuR expression by siRNA prevented atazanavir-induced increase of TNF-alpha and IL-6. These results suggest that HuR might have an impact on pathophysiological processes of HIV PI-induced atherosclerosis.
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PMID:HIV protease inhibitors increase TNF-alpha and IL-6 expression in macrophages: involvement of the RNA-binding protein HuR. 1753 Dec 41


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