CYP3; HIV-1

Atazanavir has excellent oral bioavailability in the range of 60-70%

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.

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.

[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]. Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease. Signal Transduct Target Ther. 2021 May 29;6(1):212.

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

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

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; 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.)