Effects Of Atazanavir Research Articles

Effects of atazanavir, darunavir, and raltegravir on fat and muscle among persons living with HIV

Background Antiretroviral therapy (ART) is associated with gain in quantity of fat and muscle, but the impact on quality is less understood. The objective of this study was to compare fat and muscle density among people with HIV (PWH) on stable raltegravir (RAL), atazanavir with ritonavir (ATV/r), or darunavir with ritonavir (DRV/r), and explore implications on muscle function. Methods Participants from the Modena HIV Metabolic Clinic taking RAL, ATV/r, or DRV/r with at least 1 computed tomography (CT) scan were included. CT scans were reanalyzed for area and density of truncal fat and musculature. Multivariate models explored the effect of ART on fat and muscle density. Results One hundred six participants were receiving ATV/r, 48 DRV/r, and 141 RAL. In multivariate models (reference ATV/r), only DRV/r was associated with greater subcutaneous (SAT) and visceral adipose tissue (VAT) area, lower lateralis muscle density (more fat), and greater lateralis intermuscular fat area. Compared to ATV/r, RAL was independently associated with less psoas intermuscular fat area. Among all, greater paraspinal muscle density correlated with better physical function. No associations between ART group and physical function were seen among men; DRV/r was associated with stronger grip strength among women. Conclusion DRV/r was associated with greater fat area and lower density of both fat and muscle, and RAL with less intermuscular psoas fat. Higher density psoas and paraspinal musculature were associated with better physical function, suggesting potential clinical relevance of these findings.

Drug- and Drug Abuse-Associated Hyperbilirubinemia: Experience With Atazanavir.

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.

An Unexpected Effect of Atazanavir on Carotid Wall Thickness

HIV-infected patients are at increased risk for cardiovascular disease (CVD). Some antiretroviral agents have been associated with CVD in observational studies, but randomized, prospective data are lacking. Now, investigators have analyzed changes in carotid intima-media thickness (IMT), a marker for future CVD, in a subset of participants in ACTG A5257. This randomized trial compared ritonavir-boosted atazanavir, ritonavir-boosted darunavir, and raltegravir, each combined with tenofovir/FTC, for initial HIV …

High prevalence of the UGT1A1*28 variant in HIV-infected individuals in Greece

Hyperbilirubinaemia with or without jaundice is one of the side effects of atazanavir boosted with low-dose ritonavir (ATV/rit) related to the drug plasma levels, as a result of its metabolism by UGT1A1 - uridine diphosphate-glucuronosyl transferase. Genotyping for UGT1A1*28 before initiation of antiretroviral therapy containing atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia. Our objective was to estimate the prevalence of the UGTA1A1*28 polymorphism in HIV-infected individuals in Greece and to determine its potential association with hyperbilirubinaemia in patients receiving ATV/rit. The prevalence of the UGTA1A1*28 variant was estimated in 79 HIV-infected patients prior to the administration of the first-line treatment. The UGTA1A1*28 variant was detected in 46 out of 79 individuals (58.2%). Antiretroviral therapy was administered to 64/79 patients (81%). Among them, 26/64 (40.6%) received ATV/rit. Of the ATV/rit-treated patients, 14 were found to be carriers of the UGT1A1*28 variant (54%), and maximum serum bilirubin levels were significantly higher in the carrier population (4.71 vs. 2.69 mg/dL, p = 0.026). In 50% of the population, maximum levels were recorded in the first month of follow-up. Although carriage of UGT1A1 is linked with the development of hyperbilirubinaemia, the implementation of a pharmacogenomic approach in clinical practice cannot yet be recommended as a standard of care.

Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next‐generation HIV integrase inhibitor, S/GSK1349572

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. 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. 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. 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.

Effects of Ritonavir-Boosted Darunavir, Atazanavir and Lopinavir on Adipose Functions and Insulin Sensitivity in Murine and Human Adipocytes

Ritonavir-boosted protease inhibitors (PIs) could adversely affect metabolism and adipose tissue to different extents, depending on the molecule. Using drugs with minimal adverse metabolic effects is an important consideration in at-risk HIV-infected patients. In vitro adipocyte models can be useful for comparing the effects of different PIs. We compared the effects of darunavir, darunavir/ritonavir, atazanavir/ritonavir and lopinavir/ritonavir in murine and human adipocytes on differentiation, mitochondrial function, reactive oxygen species (ROS) production and insulin sensitivity. In human and murine adipocytes, differentiation evaluated by lipid content and protein expression of adipogenic markers, mitochondrial function evaluated by aggregation of the cationic dye JC-1 and by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide lysis, and mitochondrial mass evaluated by MitoTracker fluorescence and the expression of mitochondrial proteins were unaffected by darunavir, mildly affected by darunavir/ritonavir and further altered by atazanavir/ritonavir and lopinavir/ritonavir. ROS production was unaltered by darunavir and darunavir/ritonavir but was increased by lopinavir/ritonavir and atazanavir/ritonavir. Regarding insulin sensitivity, darunavir and darunavir/ritonavir had no significant effect on insulin activation of protein kinase B (Akt/PKB) and MAP kinase and of glucose transport, whereas lopinavir/ritonavir and atazanavir/ritonavir partly impaired the effect of insulin. The effect of atazanavir/ritonavir was generally milder than that of lopinavir/ritonavir. The various PIs differentially modified adipocyte functions. Darunavir alone did not affect adipocyte functions and only modestly altered differentiation and mitochondrial function when associated with ritonavir. Lopinavir/ritonavir adversely affected differentiation and lipid content, mitochondrial function, ROS production and insulin sensitivity, and the effect of atazanavir/ritonavir was intermediate. Thus, in vitro, darunavir/ritonavir presented a safer metabolic profile on adipocytes than atazanavir/ritonavir and lopinavir/ritonavir.

Exposure-Related Effects of Atazanavir on the Pharmacokinetics of Raltegravir in HIV-1-Infected Patients

Raltegravir (RAL) is primarily metabolized by uridine diphosphate-glucorunosyl transferase 1A1 (UGT1A1). Atazanavir (ATV), a strong inhibitor of UGT1A1, has been shown to increase plasma concentrations of RAL by approximately 50% in healthy volunteers. However, the extent of this interaction has not been studied in HIV-infected patients. A pharmacokinetic study was performed in 22 HIV-infected adults treated with 400 mg RAL plus 300 mg ATV 300 twice a day. Both drugs showed high pharmacokinetic variability (RAL AUC 0-12 7649 ± 4862 ng*h/mL; ATV AUC 0-12 = 19237 ± 13136 ng*h/mL). Notably, RAL trough concentrations were significantly higher compared with those measured in HIV subjects (n = 24) on RAL plus nucleoside reverse transcriptase inhibitors (506 ± 411 versus 177 ± 262 ng/mL, P < 0.01). A significant correlation was found between RAL and ATV area under the curve (AUC) (r = 0.611, P = 0.005). Notably, patients with ATV AUC 0-12 above the mean or with concentrations exceeding the half maximal inhibitory concentration for UGT1A1 had twofold higher RAL AUCs compared with patients with lower ATV exposure. Coadministration of ATV significantly increased plasma concentrations of RAL, especially in HIV-1-infected patients exposed to high concentrations of the protease inhibitor. This pharmacokinetic drug interaction could be handled by routine measurements of ATV trough concentrations and by the assessment of plasma RAL concentrations 2 to 3 hours after the morning drug intake.

Effect of atazanavir and ritonavir on the differentiation and adipokine secretion of human subcutaneous and omental preadipocytes

Treatment of HIV with some protease inhibitors has been associated with dyslipidemia, insulin resistance and fat redistribution. It has been hypothesized that some protease inhibitors may alter the differentiation of subcutaneous and visceral adipocytes in a disparate manner. The aim of this study was to investigate whether isolated human preadipocytes display regio-specific sensitivity to the effects of ritonavir and atazanavir by examining differentiation, as well as adipokine secretion, following a 10-day drug exposure. Paired subcutaneous and omental human preadipocytes (n = 8) were induced to differentiate for 6 days, before being exposed to atazanavir or ritonavir (1-10 micromol/l) for 10 days. Lipid metabolism was assessed by Oil Red O staining and glycerol 3-phosphate dehydrogenase enzyme activity, whereas leptin and adiponectin secretion were assessed by enzyme-linked immunosorbent assay. There was no difference in differentiation between subcutaneous and omental adipocytes. Repeated exposure to ritonavir, but not to atazanavir, led to significant reductions in adipocyte differentiation. There were no differences in adiponectin secretion for any of the atazanavir treatments in both subcutaneous and omental adipocytes, whereas significant reductions were evident at 10 mumol/l for ritonavir exposed subcutaneous adipocytes. In contrast, both atazanavir and ritonavir were associated with altered leptin secretion. Ritonavir, but not atazanavir exposure, can inhibit differentiation of subcutaneous and omental adipocytes to a similar extent. Regio-specific differences, however, were apparent for adiponectin and leptin secretion. The role of region-specific alterations in adipokine secretion and apoptosis in the pathogenesis of HIV-lipodystrophy requires further attention.

The Effect of Atazanavir and Atazanavir/Ritonavir on UDP-Glucuronosyltransferase Using Lamotrigine as a Phenotypic Probe

Atazanavir (ATV) is known to inhibit UGT1A1-mediated glucuronidation. Here we report the effect of ATV and ATV/ritonavir (RTV) on another UGT1A isoenzyme, UGT1A4. Twenty-one healthy volunteers received a single dose of 100 mg of oral lamotrigine on days 1, 13, and 27; on each occasion blood was sampled before the dose was administered and through 120 h after ingestion of the drug. On days 8-17 the subjects received oral ATV 400 mg q.d. On days 18-30 the subjects received oral ATV 300 mg plus oral RTV 100 mg q.d. Seventeen subjects were evaluable for pharmacokinetic analysis. Geometric mean ratios (+90% confidence intervals (CIs)) of lamotrigine area under the plasma concentration-time curve (AUC)(0-inf) and peak plasma concentration (C(max)) for ATV + lamotrigine and for lamotrigine alone were 0.88 (0.86-0.91) and 0.99 (0.95-1.02), respectively; the corresponding ratios for ATV/RTV and for lamotrigine were 0.68 (0.65-0.70) and 0.94 (0.90-0.97), respectively. The mean ratio of lamotrigine-2N-glucuronide to lamotrigine AUC(0-inf) increased from 0.45 for lamotrigine to 0.71 for ATV/RTV + lamotrigine. ATV alone does not significantly influence glucuronidation of lamotrigine. In contrast, ATV/RTV results in moderately decreased exposure to lamotrigine.

Interindividual variability in the effect of atazanavir and saquinavir on the expression of lymphocyte P-glycoprotein

ABCB1 encodes the efflux transporter P-glycoprotein (P-gp), which regulates the intracellular concentration of many xenobiotics, including several HIV protease inhibitors (PIs). Exposure to some xenobiotics, such as the antibiotic rifampicin, increases P-gp expression. In the present study, we investigated the effect of the HIV PIs saquinavir and atazanavir on the expression and function of ABCB1 and P-gp in primary and cultured lymphocytes, as well as the molecular interactions between these drugs and P-gp. ABCB1 and P-gp expression and function were examined in lymphocyte samples from healthy subjects before and after atazanavir-boosted saquinavir treatment. Expression and function were also studied in CEM cells following exposure to atazanavir and saquinavir. The inhibitory effects of these drugs were investigated in ABCB1-transfected HEK293T cells. P-gp expression and function were measured by flow cytometry. ABCB1 mRNA expression was evaluated using quantitative RT-PCR. There were no overall changes in ABCB1 or P-gp expression or function after saquinavir-atazanavir treatment in primary lymphocyte samples. However, there was considerable interindividual variability in baseline lymphocyte ABCB1 expression, as well as in the degree of change in ABCB1 expression after saquinavir-atazanavir administration. In cell culture, 5 microM saquinavir increased ABCB1 levels, although it did not affect P-gp expression. Atazanavir inhibited P-gp function at concentrations above therapeutic levels. Differences in lymphocyte ABCB1 expression, which may be caused by genetic polymorphisms in ABCB1 or its regulatory partners, are a likely cause of interindividual variation in the disposition and efficacy of clinically relevant P-gp substrates, including HIV PIs.

Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV-infected patients

To examine cellular and plasma concentrations of atazanavir when given in combination with saquinavir/ritonavir in HIV+ patients. Twelve HIV+ patients were receiving saquinavir/atazanavir/ritonavir 1600/200/100 mg once daily and venous blood samples were taken to determine cellular and plasma concentrations of each protease inhibitor at 2, 6, 12 and 24 h. Peripheral blood mononuclear cells were separated by density gradient centrifugation. The ratio of the cellular AUC0-24/plasma AUC0-24 was calculated to determine cellular drug accumulation. Lymphocyte P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) expression was determined by flow cytometry. Nine of the patients had previously received a regimen of saquinavir/ritonavir 1600/100 mg; therefore the effect of atazanavir on the cellular and plasma pharmacokinetics of saquinavir and ritonavir was examined. In vivo cellular and plasma determinations of saquinavir, atazanavir and ritonavir gave accumulation ratios of 4.9, 1.2 and 1.7, respectively. There was no relationship between saquinavir, atazanavir or ritonavir accumulation and P-gp, MRP1 or BCRP expression. When comparing pharmacokinetic values in the nine patients receiving saquinavir/ritonavir with and without atazanavir, the median cellular saquinavir AUC0-24 was significantly increased (34.9-117.2 mg.h/L) on addition of atazanavir (P=0.004). The C24 of saquinavir in plasma and cells was significantly higher with atazanavir (plasma C24 0.05 versus 0.14 mg/L with atazanavir; cellular C24 0.61 versus 2.03 mg/L with atazanavir, P=0.02). The mechanism of differential intracellular protease inhibitor accumulation is unclear. Co-administration of atazanavir caused an increase in both the plasma and cellular exposure (AUC0-24) and C24 of saquinavir but not ritonavir.

ATAZANAVIR: EFFECTS ON P-GLYCOPROTEIN TRANSPORT AND CYP3A METABOLISM IN VITRO

The effect of atazanavir on P-glycoprotein (P-gp) expression and activity, as well as its inhibitory potency against CYP3A activity, was evaluated in vitro. Induction of P-gp activity and expression was studied using LS180V cells. P-gp inhibition was studied using both LS180V cells and Caco-2 cells. P-gp activity was assessed by measuring P-gp-mediated rhodamine 123 (Rh123) transport, and P-gp expression was determined using SDS-polyacrylamide gel electrophoresis/Western blot analysis. CYP3A inhibition was tested using triazolam hydroxylation in human liver microsomes (HLM). Extended (3-day) exposure of LS180V cells to 30 microM atazanavir caused a 2.5-fold increase in immunoreactive P-gp expression as well as a concentration-dependent decrease of intracellular Rh123 to a mean 45% (S.D. 5.2%) of control. Acute exposure (2 h) of LS180V cells to atazanavir increased intracellular Rh123 concentrations up to 300% of control at 100 microM atazanavir. At 30 microM and above, acute atazanavir exposure reversed P-gp induction caused by 3-day pretreatment with 10 microM ritonavir. P-gp inhibition was also observed in Caco-2 cells, causing an effect comparable to that observed for the known P-gp inhibitor verapamil (50% of control). In HLM, atazanavir was an inhibitor of triazolam hydroxylation, with inhibitory potency greatly increased by preincubation. IC50 values with and without preincubation were 0.31 microM (S.D. 0.13) and 5.7 microM (S.D. 4.1), respectively. Thus, atazanavir is an inhibitor and inducer of P-gp as well as a potent inhibitor of CYP3A in vitro, suggesting a potential for atazanavir to cause drug-drug interactions in vivo.