CYP3; HIV-1

In vitro activity: Atazanavir inhibits the proteolytic cleavage of the viral gag precursor p55 polyprotein with IC50 of ~47 nM in virus-infected H9 cells. Atazanavir exhibits potent antiviral activity with EC50 of 3.89 nM in RF/MT-2 strains. Atazanavir is shown to be an inhibitor of bilirubin glucuronidation with IC50 of 2.4 μM. Atazanavir inhibits recombinant UGT1A1 with Ki of 1.9 μM. Atazanavir inhibits cell growth in U251, T98G, and LN229 glioblastoma cell lines, with strikingly increased GRP78 and CHOP protein levels. Atazanavir causes a prominent increase of polyubiquitinated proteins of various different sizes in U251 glioblastoma cells. Atazanavir also inhibits human 20S proteasome with IC50 of 26 μM. Atazanavir (30 μM) changes the magnitudes of ER stress and UPR gene expression in HepG2 cells. Atazanavir (30 mM) causes a 2.5-fold increase in immunoreactive P-gp expression with decreased intracellular Rh123 in LS180V cells.
Kinase Assay: To determine the inhibition constants (Ki) for each Prt inhibitor, purified HIV-1 RF wild-type Prt (2.5 nM) is incubated at 37 ℃ with 1 μM to 15 μM fluorogenic substrate in reaction buffer (1 M NaCl, 1 mM EDTA, 0.1 M sodium acetate [pH 5.5], 0.1% polyethylene glycol 8000) in the presence or absence of Atazanavir. Cleavage of the substrate is quantified by measuring an increase in fluorescent emission at 490 nM after excitation at 340 nM using a Cytofluor 4000. Reactions are carried out using 1.36 μM, 1.66 μM, 2.1 μM, 3.0 μM, 5.0 μM, or 15 μM substrate in the presence of five concentrations of Atazanavir (1.25 nM to 25 nM). Substrate cleavage is monitored at 5-min intervals for 30 min. Cleavage rates are then determined for each sample at early time points in the reaction, and Ki values are determined from the slopes of the resulting Michaelis-Menten plots.
Cell Assay: To determine cytotoxicity, host cells are incubated in the presence of serially diluted Atazanavir for 6 days and cell viability is quantitated using an XTT[2,3-bis(2-methoxy-4-nitro-5-sulfophenyl-2H-tetrazolium-5-carboxanilide] assay to calculate the 50% cytotoxic concentrations (CC50s). To assess the effect of human serum proteins on antiviral activity, the 10% fetal calf serum normally used for assays is replaced with 40% adult human serum or 1 mg of α1-acid glycoprotein/mL.

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Effects of Atazanavir on rCFs proliferation, collagen production and proteins expression [3]
The rCFs were examined in the absence or the presence of CoCl2 to mimic a pro-fibrotic environment during hypoxic conditions. Following CoCl2 induced hypoxia, rCFs proliferation increased compared with the normal group (P < 0.01), as shown in Table 1, but was significantly inhibited in a concentration-dependent manner following Atazanavir sulfate treatment at concentrations between 1 and 10 μM compared with the CoCl2 group (P < 0.05). To further characterize this inhibitory effect, atazanavir sulfate treatment was combined with HCQ, a TLR 9 antagonist. However, it found no further decline in rCFs proliferation compared with the HCQ group (P > 0.05), as shown in Table 1. In addition, the content of collagen I and collagen III was measured in CoCl2 stimulated rCFs. The results showed the contents of collagen I and collagen III were increased compared with the normal group (P < 0.01). However, collagen I and collagen III levels were significantly reduced in a concentration-dependent manner following atazanavir sulfate treatment at concentrations between 1 and 10 μM compared with the CoCl2 group (P < 0.05)), as shown in Table 1. It found no further decline in collagen I and collagen III in atazanavir 3 μM plus HCQ 3 μM compared with the HCQ group (P > 0.05), as shown in Table 1.

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To further examine the mechanism of Atazanavirsulfate on reducing rCFs proliferation during hypoxia, we investigated the expression of HMGB1, p-NF-κB, p-IκBα and total NF-κB with or without atazanavir sulfate. Following CoCl2 induced hypoxia, HMGB1, p-NF-κB, p-IκBα and TLR 9 expression were increased compared with the normal group (P < 0.01), as shown in Fig. 1A and B, but HMGB1, p-IκBα and p-NF-κB expression were significantly inhibited following atazanavir sulfate treatment at 1–10 μM compared with the CoCl2 group (P < 0.05 or P < 0.01). Compared with the CoCl2 group, Atazanavir 3 μM group has no change in total NF-κB expression, and no decline in TLR 9 expression (P > 0.05), as shown in Fig. 1A and B. HCQ treatment reduced HMGB1, p-NF-κB and TLR 9 expression (P < 0.05 or P < 0.01). Atazanavir treatment was combined with HCQ has no further decline in HMGB1, TLR 9 and p-NF-κB expression (P > 0.05) compared with the HCQ group (P > 0.05), as shown in Fig. 1C and D. These findings suggest that atazanavir attenuates hypoxia induced rCFs proliferation by modulating the HMGB1/TLR 9 pathway.

Effects of Atazanavir sulfate on myocardial function [3]
We evaluated the effect of Atazanavir on LVSP and ± dp/dtmax of the left ventricle after MI 28 days. Compared with vehicle-treated animals, rats treated with Atazanavir had significantly improved LVSP, + dp/dtmax and − dp/dtmax 28 days after MI as shown in Table 2. In addition, we found no further change in SP, DP and HR compared with the HCQ group (P > 0.05). It is clear that continuous atazanavir treatment 28 days provided long-term benefits for the myocardial function recovery after MI.

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Effects of Atazanavir on cardiac collagen volume and myocytes hypertrophy after MI 28 days [3]
To clarify the mechanism of long-term improved cardiac performance caused by atazanavir, we examined the effects of atazanavir treatment on mural hypertrophy and collagen volume in the non-infarcted region and infarct size. There was no difference in infarct size between the vehicle-treated group and atazanavir 30 mg/kg group (38.11 ± 4.15% and 38.80 ± 4.62%, respectively). The cross-sectional area and diameter of myocytes in the non-infarcted LV and hypertrophy of the myocytes significantly increased in vehicle-treated rats compared with Sham rats, while inhibited by atazanavir, as shown in Fig. 2A, C and D. Atazanavir significantly attenuated an increase in morphometrical collagen volume fraction in the border left ventricle, as shown in Fig. 2B and E. In agreement with the above results, the heart index (heart-weight to body-weight ratio) which was increased in the vehicle-treated rats compared with sham rats, was significantly (p < 0.05) lowered by continuous atazanavir treatment, as shown in Fig. 2F.

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Effects of Atazanavir on the expressions of α-SMA, HMGB1, p-NF-κB, TLR 9, collagen I, collagen III and the content of Hyp in vivo [3]
Changes in the expressions of α-SMA, HMGB1, TLR 9, p-NF-κB, collagen I and collagen III were also examined by Western blot analysis, as shown in Figs. 3–5. In vehicle-treated rats, all of the examined protein expressional levels and the content of Hyp increased relative to the sham animals (P < 0.01), while those protein expressional levels and the content of Hyp decreased following Atazanavir treatment compared with the vehicle-treated rats (P < 0.01). The results of in vitro and in vivo investigations suggest that atazanavir can reduce fibroblast proliferation and collagen deposition by modulating the HMGB1/TLR 9 pathway.

Purified HIV-1 RF wild-type Prt (2.5 nM) is incubated at 37 °C with 1 μM to 15 μM fluorogenic substrate in reaction buffer (1 M NaCl, 1 mM EDTA, 0.1 M sodium acetate [pH 5.5], 0.1% polyethylene glycol 8000) with or without atazanavir in order to calculate the inhibition constants (Ki) for each Prt inhibitor. Using a Cytofluor 4000, cleavage of the substrate is measured as an increase in fluorescent emission at 490 nM following excitation at 340 nM. In five different concentrations of Atazanavir (1.25 nM to 25 nM), reactions are conducted with substrate that is 1.36 μM, 1.66 μM, 2.1 μM, 3.0 μM, 5.0 μM, or 15 μM. During a half-hour, the substrate cleavage is observed every five minutes. Then, at early stages of the reaction, cleavage rates are calculated for each sample, and Ki values are ascertained from the slopes of the ensuing Michaelis-Menten plots.

Cell culture and expressional analysis [3]
Rat cardiac fibroblasts (rCFs) from newborn (1- to 2-day-old) Sprague-Dawley rats were isolated according to previous method (Villarreal et al., 1993). Cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) with 10% fetal bovine serum, 100 kU/L penicillin and 100 mg/L streptomycin at 37 °C with 5% CO2 in a humidified incubator. The cells were cultured to approximately 70% confluency and starved in serum-free DMEM overnight prior to the treatment. The cells were then treated with 3 μM Atazanavir sulfate (purity > 99.0%; CAS No.: 229975-97-7) with or without cobalt chloride (CoCl2; 100 μM) for 72 h and thereafter proteins were extracted.

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rCFs proliferation assay and expressional assessment [3]
To assess cellular proliferation, rCFs were maintained as described above. Cells were exposed to CoCl2 at 100 μM to mimic hypoxia and treated with varying concentrations of Atazanavir (0, 1, 3, 10 μM) with or without 3 μM hydroxychloroquine (HCQ), a TLR 9 antagonist, for 72 h. Cellular proliferation levels were determined via cell counting. To examine changes in expression, the cells were seeded into 6-well flat bottom plates and maintained as described above, with one well per plate maintained as an untreated control. Cells were treated with 3 μM Atazanavir sulfate with or without CoCl2 (100 μM) for 72 h and thereafter the supernatants were collected and the proteins were extracted. Collagen I and collagen III were examined by ELISA kits. The expression levels of TLR 9, HMGB1, p-NF-κB, p-IκBα and total NF-κB were examined by Western blot and normalized and displayed as described above. To investigate the possible mechanism of reduction in rCF proliferation, cells were treated with 3 μM atazanavir sulfate with or without 3 μM HCQ for 72 h, TLR 9 and expression levels of HMGB1 and p-NF-κB were examined using Western blot as described above.

Induction of myocardial infarction (MI) model and experimental assessment [3]
Briefly, Rats were anesthetized with ketamine 100 mg/kg (i.m.) and xylazine 10 mg/kg (i.m.) and ventilated with room air using a rodent respirator. The chest was opened by middle thoracotomy and the left coronary artery was ligated at 2–3 mm from its origin between the left atrium and pulmonary artery conus using a 6-0 prolene suture. A successful operation was confirmed by the occurrence of ST-segment elevation in an electrocardiogram. This operation was performed by an experimenter who was blinded to the group assignments of the animals to avoid subjective bias of the experimenter on the outcome. The sham-operated group underwent thoracotomy and cardiac exposure without coronary ligation. Thirty rats were divided into three groups including (I) non-MI rats; (II) MI rats received saline alone; (III) MI rats received intragastric administration of Atazanavir sulfate (30 mg/kg) plus ritonavir (10 mg/kg). Atazanavir is a low oral bioavailability compound and, clinically, is generally coadministrated with Ritonavir, which boosts the oral bioavailability of atazanavir by inhibiting cytochrome P450 (CYP) 3A4, and P-glycoprotein via the same metabolic pathway (Le Tiec et al., 2005, 021567s026lbl). The rats were administered daily via intragastric administration of corresponding drug for continuous 28 days after MI 24 h. Treatment was orally administered on a daily basis for atazanavir-treated animals, while animals in the vehicle-treated and sham groups were given an equal volume of saline. At day 29, determine hemodynamics and analyze histopathological change.

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Dissolved in a mixture of ethanol, polyethylene glycol 200, and 5% glucose (2:6:2); 10 mg/kg; i.v.

The WT mice (FVB/NTac strain), TKO mice (FVB/N7 strain)

Absorption, Distribution and Excretion
Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. A steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of atazanavir with either a light or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state. Coadministration of a single 300-mg dose of atazanavir and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.
Following a single 400-mg dose of ¹⁴C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drugs accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively.
In patients with HIV infection, the volume of distribution of atazanavir was estimated to be 88.3 L.
In patients with HIV infection, the clearance of atazanavir was estimated to be 12.9 L/hr.
Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200-800 mg once daily. Steady-state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold.
Administration of /atazanavir/ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single dose of /atazanavir/ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single dose of /atazanavir/ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of /atazanavir/ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one half compared to the fasting state.
Peak plasma concentration: Healthy subjects: 5199 ng/mL on day 29 following a 400 mg daily dose with a light meal. HIV-infected patients: 2298 ng/mL on day 29 following a 400 mg daily dose with a light meal.
Time to peak concentration: HIV-infected patients: 2 hours.
For more Absorption, Distribution and Excretion (Complete) data for ATAZANAVIR (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.
Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and (atazanavir sulfate) dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.

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Biological Half-Life
The mean elimination half-life of atazanavir in healthy subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal. Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg dose).
The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared with 6.4 hours in healthy volunteers. ...
The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

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Pharmacokinetics & metabolism [2]
Atazanavir is rapidly absorbed after oral administration (Tmax 2.5 h) and demonstrates nonlinear pharmacokinetics, resulting in greater than dose-proportional increases in bioavailability (AUC and Cmax) over a dose range of 200–800 mg daily. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Once absorbed, atazanavir is highly bound to plasma proteins α1-acid glycoprotein and albumin to similar extents (89 and 86%, respectively). Atazanavir is extensively metabolized by the hepatic cytochrome P450 (CYP) system to form two main inactive metabolites and is both a substrate and inhibitor of the CYP3A4 isoenzyme. In vitro studies have also demonstrated that atazanavir is both an inhibitor and inducer of the P-glycoprotein ATP-dependent efflux pump, which has a wide cellular distribution and a broad substrate specificity, further increasing its potential for drug-drug interactions and variable pharmacokinetics in vivo [17]. Atazanavir should therefore be used with caution in patients taking strong CYP3A4 inhibitors, moderate or strong CYP3A4 inducers and major CYP3A4 substrates. Coadministration with drugs that induce CYP3A4, such as rifampicin, may decrease atazanavir plasma concentrations and reduce clinical effect, while drugs that inhibit CYP3A4 may elevate atazanavir levels and increase toxicity.
The mean elimination half-life of atazanavir 400 mg taken with food is approximately 7–8 h at steady state with 20 and 7% of active drug eliminated in feces and urine, respectively.
In vitro studies have indicated that a direct inhibition of UGT1A1-mediated bilirubin glucuronidation by free, nonproteinbound atazanavir gives a mechanistic rationale for dose-related hyperbilirubinemia. Indinavir may similarly inhibit UGT1A and coadministration with atazanavir is not recommended.
Large inter- and intrapatient variability in atazanavir plasma concentrations have been demonstrated in population pharmacokinetic studies, yet the same dose of atazanavir is currently administered regardless to differences in systemic blood and tissue disposition. The therapeutic range of atazanavir lies between 150 and 850 ng/ml [21,102]; however, plasma levels in the absence of RTV have been reported to be frequently lower than the target Cmin of 150 ng/ml in both patients and substance. The wide interpersonal variability in atazanavir exposure has been considered an indication for twice daily dosing or therapeutic drug monitoring. However, no significant relationship has been established between atazanavir plasma trough concentration (Cmin) and antiviral response in patients starting atazanavir without PI mutations. The wide variability in atazanavir exposure strongly supports the preferable use of RTV-boosted atazanavir in PI-experienced individuals.

Interactions
Pharmacologic interaction with bepridil (potential for serious and/or life-threatening adverse effects). Concomitant use of bepridil and atazanavir not recommended.
Pharmacokinetic interaction with antiarrhythmic agents (i.e., amiodarone, systemic lidocaine, quinidine). Potential for serious and/or life-threatening adverse effects. Monitor plasma concentrations of these antiarrhythmic agents if used concomitantly with atazanavir.
Potential pharmacokinetic interaction (increased plasma concentration of the tricyclic antidepressant). Potential for serious and/or life-threatening adverse effects. Monitor plasma concentrations of these tricyclic antidepressants agents if used concomitantly with atazanavir.
Pharmacokinetic interaction with rifampin (substantial decrease (90%) in the peak plasma concentration and area under the concentration-time curve (AUC) of HIV protease inhibitors). Concomitant use of atazanavir and rifampin not recommended.
For more Interactions (Complete) data for ATAZANAVIR (34 total), please visit the HSDB record page.

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Toxicity Summary
Currently, no specific antidote exists for atazanavir toxicity. Patients should receive symptomatic and supportive care from healthcare staff while regularly monitoring their vital signs and looking for signs of respiratory distress. Electrocardiogram monitoring of the patient is recommended, as atazanavir may exacerbate AV block due to PR interval prolongation. In cases where a simultaneous overdose with nucleoside reverse transcriptase inhibitors is suspected, clinicians should carefully monitor patients for symptoms of lactic acidosis.

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Hepatotoxicity
Atazanavir can cause several forms of liver injury including transient serum enzyme elevations, indirect hyperbilirubinemia, idiosyncratic acute liver injury and exacerbation of underlying chronic viral hepatitis.
Some degree of serum aminotransferase elevations occurs in a high proportion of patients taking atazanavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication.
Atazanavir therapy (similar to indinavir) also causes increases in unconjugated (indirect) and total serum bilirubin that can manifest as jaundice in up to 10% of patients. These elevations are due to the inhibition of UDP glucuronyl transferase, the hepatic enzyme responsible for conjugation of bilirubin that is deficient in Gilbert syndrome. The hyperbilirubinemia is usually mild, the increases averaging 0.3-0.5 mg/dL, but can be more marked in patients with Gilbert syndrome with increases of 1.5 mg/dL or more and clinical jaundice. The jaundice, however, is not indicative of hepatic injury.
Clinically apparent acute liver injury due to atazanavir is rare and the clinical pattern of liver injury, latency and recovery have not been well defined. The liver injury is idiosyncratic and rare and probably similar to the injury that is caused by other HIV protease inhibitors. The liver injury typically arises 1 to 8 weeks after starting the protease inhibitor and has variable patterns of liver enzyme elevation, from hepatocellular to cholestatic. Signs of hypersensitivity (fever, rash, eosinophilia) are rare, as is autoantibody formation. The acute liver injury is usually self-limited and resolves within a few weeks of stopping the antiretroviral agent (Case 1).
In addition, initiation of atazanavir based antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy, and associated with a hepatocellular pattern of serum enzyme elevations and increases in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Atazanavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Amounts of atazanavir in milk appear to be low based on limited data. The combination product, which also contains the CYP3A inhibitor cobicistat, has not been studied during breastfeeding, but would be expected to have similar or greater levels of atazanavir in milk. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.

◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk
Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Adverse Effects
Common adverse effects of atazanavir include hyperbilirubinemia (35% to 49% in adults and 16% in children), rash (up to 21%), hypercholesterolemia (6% to 25%), hyperamylasemia (14% to 33%), jaundice (5% to 9% in adults and 13% to 15% in children), nausea (3% to 14%), cough (21% in children), and fever (2% in adults and 18% to 19% in children). Severe adverse effects include Stevens-Johnson syndrome, toxic skin eruptions, erythema multiforme, angioedema, cholecystitis, pancreatitis, interstitial nephritis, diabetic ketoacidosis, and AV block. Additional potential adverse effects include nephrolithiasis, cholelithiasis, hyperlipidemia, hypertriglyceridemia, bleeding, pancreatitis, exacerbation of diabetes mellitus or hyperglycemia, and lactic acidosis when used in combination with nucleoside analogs.
Although immune reconstitution inflammatory syndrome (IRIS) is not a direct adverse effect of atazanavir, it is noteworthy that a pathological inflammatory response may occur after initiating antiretroviral treatment for HIV infection. There have been reports of up to a 75% mortality rate in IRIS cases associated with tuberculosis in the central nervous system. Although there have been suggestions that successful treatment with antiretroviral drugs enables the recovery of immune function, it may also exacerbate existing opportunistic infections (paradoxical IRIS) or reveal previously undetected opportunistic infections (unmasking IRIS).
Clinical symptoms may vary based on the type of opportunistic infections, but a common feature includes acute generalized or local inflammatory responses, such as fever or localized tissue edema. Therefore, the timing of initiating antiretroviral therapy is crucial to prevent IRIS.

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Drug-Drug Interactions
Atazanavir is metabolized through the CYP3A4 pathway and has inhibitory effects on CYP3A4, CYP1A2, and CYP2C9 enzymes. Therefore, patients taking medications that inhibit or are substrates of these enzymes, especially those with a narrow therapeutic index, should avoid atazanavir. Significant drug interactions may arise with warfarin, irinotecan, diltiazem, simvastatin, lovastatin, phosphodiesterase inhibitors, St John's wort, and tenofovir.

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Protein Binding
Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively).

[1]. Atazanavir: new option for treatment of HIV infection. Clin Infect Dis. 2004 Jun 1;38(11):1599-604.

[2]. Atazanavir: its role in HIV treatment. Expert Rev Anti Infect Ther. 2008 Dec;6(6):785-96.

[3]. Long-term oral atazanavir attenuates myocardial infarction-induced cardiac fibrosis. Eur J Pharmacol . 2018 Jun 5:828:97-102.

Therapeutic Uses
Atazanavir sulfate is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. The use of atazanavir sulfate may be considered in antiretroviral-treatment experienced adults with HIV strains that are expected to be susceptible to atazanavir sulfate by genotypic and phenotypic testing. /Included in US product labeling/

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Drug Warnings
Lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have been reported in patients receiving atazanavir in conjunction with nucleoside reverse transcriptase inhibitors (NRTIs). Therapy with NRTIs is known to be associated with an increased risk of lactic acidosis syndrome; female gender and obesity also are known risk factors for this syndrome. Whether atazanavir contributes to the risk of lactic acidosis syndrome remains to be established.
Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus has been reported in patients receiving HIV protease inhibitors. May require initiation of antidiabetic therapy (e.g., insulin, oral antidiabetic agents) or dosage adjustment for existing diabetes; diabetic ketoacidosis can occur.
Abnormalities in AV conduction, including prolongation of the PR interval, have occurred in individuals receiving atazanavir. Cardiac conduction abnormalities generally are limited to first-degree AV block; prolongation of the QTc interval observed in HIV-infected patients receiving atazanavir have not been directly attributed to the drug. Asymptomatic first-degree AV block was observed in 5.9 or 3-10.4% of patients in clinical trials receiving regimens that included atazanavir or comparator antiretrovirals (lopinavir/ritonavir, nelfinavir, efavirenz), respectively; second- or third-degree block was not observed. Atazanavir should be used with caution in patients with cardiac conduction abnormalities (e.g., marked first-degree AV block; second- or third-degree AV block) because of lack of clinical experience.
Because atazanavir is a competitive inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (an enzyme that catalyzes the glucuronidation of bilirubin), reversible asymptomatic elevations in indirect (unconjugated) bilirubin occur in most patients receiving the drug. Total bilirubin concentrations at least 2.6 times the upper limit of normal have been reported in 35-47% of patients receiving the drug in clinical trials; long-term safety data are not available for patients experiencing persistent elevations in total bilirubin exceeding 5 times the upper limit of normal. Increases in serum AST (SGOT) and/or ALT (SGPT) concentrations that occur with hyperbilirubinemia should be evaluated for etiologies other than hyperbilirubinemia. If jaundice or scleral icterus that result from bilirubin elevations cause cosmetic concerns, alternative antiretroviral therapy can be considered; reduction of atazanavir dosage not recommended (efficacy data not available for reduced dosages).
For more Drug Warnings (Complete) data for ATAZANAVIR (17 total), please visit the HSDB record page.

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Pharmacodynamics
Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Atazanavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals. Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC₅₀ values above the EC₅₀ values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture for 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram. Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec Azatanavir is a protease inhibitor (PI) approved for the treatment of HIV-1 infection. Atazanavir is a substrate and inhibitor of cytochrome P450 isozyme 3A and an inhibitor and inducer of P-glycoprotein. It has similar virologic efficacy as efavirenz and ritonavir-boosted lopinavir in antiretroviral-naive individuals. Its impact on lipids is less than other PIs and it is suitable for those in whom hyperlipidemia is undesirable. Ritonavir boosting of atazanavir enhances the bioavailability of atazanavir but may result in some elevation of lipids and is recommended for treatment-experienced patients and those receiving efavirenz or tenofovir. Ritonavir-boosted atazanavir has similar antiviral activity as ritonavir-boosted lopinavir in both antiretroviral therapy-naive and -experienced patients. Atazanavir causes unconjugated bilirubinemia in over 40% of patients but results in less than 2% discontinuations. Atazanavir is licensed for once-daily use and atazanavir/ritonavir competes with lopinavir/ritonavir as the most commonly prescribed PI.[2]

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Atazanavir is a recently approved human immunodeficiency virus (HIV) protease inhibitor that has an important role in the treatment of both antiretroviral-naive and antiretroviral-experienced individuals. Atazanavir (400 mg) can be administered once per day and requires only 2 capsules. Drug exposure can be safely increased with coadministration of a once-daily regimen of atazanavir (300 mg) and ritonavir (100 mg). Atazanavir is not associated with elevations in serum levels of total cholesterol, low-density lipoprotein cholesterol, or triglycerides, potentially reducing the need for lipid-lowering agents. Atazanavir is associated with elevations in unconjugated bilirubin levels, which are usually not dose limiting. For treatment-naive patients receiving atazanavir who experience virologic rebound, the I50L mutation in HIV protease arises, which does not confer cross-resistance to other protease inhibitors. In treatment-experienced patients with high-level resistance to other protease inhibitors, susceptibility to atazanavir is usually reduced, and optimal effects of atazanavir are seen when it is administered with ritonavir. Similar to other protease inhibitors, careful attention must be paid to drug interactions when administering atazanavir with concomitant medications. [1]

C38H52N6O7

704.86

704.389

C, 64.75; H, 7.44; N, 11.92; O, 15.89

198904-31-3

Atazanavir sulfate;229975-97-7;Atazanavir-d15;1092540-56-1;Atazanavir-d18;1092540-52-7;Atazanavir-d9;1092540-51-6;Atazanavir-d5;1132747-14-8;Atazanavir-d6;1092540-50-5; 198904-31-3

148192

White to off-white solid powder

1.2±0.1 g/cm3

207-209ºC

1.562

5.2

5

9

18

51

1110

4

O=C(OC)N[C@@H](C(C)(C)C)C(NN(CC1=CC=C(C2=NC=CC=C2)C=C1)C[C@H](O)[C@H](CC3=CC=CC=C3)NC([C@H](C(C)(C)C)NC(OC)=O)=O)=O

AXRYRYVKAWYZBR-GASGPIRDSA-N

InChI=1S/C38H52N6O7/c1-37(2,3)31(41-35(48)50-7)33(46)40-29(22-25-14-10-9-11-15-25)30(45)24-44(43-34(47)32(38(4,5)6)42-36(49)51-8)23-26-17-19-27(20-18-26)28-16-12-13-21-39-28/h9-21,29-32,45H,22-24H2,1-8H3,(H,40,46)(H,41,48)(H,42,49)(H,43,47)/t29-,30-,31+,32+/m0/s1

methyl N-[(2S)-1-[2-[(2S,3S)-2-hydroxy-3-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-4-phenylbutyl]-2-[(4-pyridin-2-ylphenyl)methyl]hydrazinyl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

Latazanavir; Zrivada; Reyataz; BMS-232632; BMS232632; Atazanavir; 198904-31-3; Latazanavir; Zrivada; Reyataz; BMS-232,632; atazanavirum; CGP 73547; BMS 232632; Atazanavir

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)