HIV-1

With an IC50 of 7.5± 0.3 nM, bictegravir (BIC) inhibits the strand transfer activity. With an IC50 of 241±51 nM, bictegravir is a much weaker inhibitor of HIV-1 IN's 3′-processing activity than it is of strand transfer activity. In comparison to the mock-treated control, bictegravir increases the accumulation of 2-LTR circles by approximately five times and decreases the quantity of real integration products in infected cells by a factor of 100. With EC50s of 1.5 and 2.4 nM, respectively, bictegravir potently inhibits HIV-1 replication in both MT-2 and MT-4 cells. With EC50s of 1.5±0.3 nM and 6.6±4.1 nM, respectively, bictegravir demonstrates strong antiviral effects in primary CD4+ T lymphocytes and monocyte-derived macrophages. These values are in line with those observed in T-cell lines.

HIV-1 IIIb is cultured in bulk on MT-2 cells for three hours at 37°C, with a cell density of 2×106 cells/mL. Bictegravir (BIC) or DMSO (mock-treated control) are given to infected MT-2 cells at a final concentration that is at least 20 times the antiviral 50% effective concentration (EC50) of each drug.The cells are harvested for total DNA isolation after these plates are incubated at 37°C for either 12 hours (for late reverse transcription product quantification) or 24 hours (for 2-LTR circle and Alu-LTR product quantification). Using the DNA minikit, DNA is extracted from each well and collected as a 100-μL eluate. The host globin gene level in each sample is used to normalize TaqMan real-time PCR-quantified 2-LTR junctions (2-LTR circles), late reverse transcription products, and integration junctions (Alu-LTR)[1].

In bulk culture, MT-2 cells are infected with HIV-1 IIIb for three hours at 37°C at a cell density of 2×106 cells/mL. Bictegravir (BIC) or DMSO (mock-treated control) are given to infected MT-2 cells at a final concentration that is at least 20 times the antiviral 50% effective concentration (EC50) of each drug. The cells are harvested for total DNA isolation after these plates are incubated at 37°C for either 12 hours (for late reverse transcription product quantification) or 24 hours (for 2-LTR circle and Alu-LTR product quantification).Using the DNA minikit, DNA is extracted from each well and collected as a 100-μL eluate. The host globin gene level in each sample serves as the standard for TaqMan real-time PCR quantification of 2-LTR junctions (2-LTR circles), late reverse transcription products, and integration junctions (Alu-LTR)[1].

Absorption, Distribution and Excretion
Bictegravir is rapidly absorbed within the body. Tmax= 2.0-4.0h
BIC is mainly eliminated through UGT1A1 glucuronidation and CYP3A4 oxidation, equally. About 1% of the bictegravir dose is excreted in the urine, unchanged.
0.2 L/Kg in humans
Bictegravir is mainly cleared by the kidneys. Those with renal clearance <30 should not take bictegravir [FDA LABEL]

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Metabolism / Metabolites
In a 10-day dose-ranging study, monotherapy (5 mg to 100 mg) once daily in adults who were not previously treated with bictegravir, the median half-life of BIC ranged from 15.9 h - 20.9 h. Bictegravir is metabolized in the liver and kidneys. CYP3A4 and UGT1A are the primary enzymes involved in the metabolism of bictegravir. Administration of bictegravir is not advised in patients with renal creatinine clearance of <30 mL/min and patients with hepatic disease [FDA LABEL].

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Biological Half-Life
Half-life is 17.3 hours.

Hepatotoxicity
In large clinical trials, therapy with bictegravir combined with emtricitabine and tenofovir alafenamide was associated with alanine aminotransferase (ALT) elevations (above 1.5 times ULN) in 11% patients, but these rates were similar to those in comparator groups (12% to 15%) receiving matched background optimized antiretroviral therapy without bictegravir. Elevations above 5 times ULN occurred in only 1.4% of bictegravir vs 0.9% to 1.3% of control comparator arm subjects. The elevations were not associated with clinical symptoms and generally did not require dose modification. In addition, there were no instances of acute hepatocellular liver injury with jaundice. The product label for bictegravir mentions acute exacerbations of hepatitis B and hepatic failure as potential adverse reactions when bictegravir with emtricitabine and tenofovir is discontinued. This adverse reaction can occur upon discontinuation of any antiretroviral regimen with concurrent activity against HBV and represents the effects of tenofovir and emtricitabine. Nevertheless, since its approval and its more widescale use, there have been no published reports of clinically apparent cases of liver injury or exacerbation of hepatitis B convincingly attributed to bictegravir.
Likelihood score: E* (unproven but suspected potential cause of liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal bictegravir 50 mg once daily produce low levels in milk and infant serum. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. 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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Protein Binding
> 99 % bound to human plasma Blood to plasma ratio: 0.64

[1]. Antimicrob Agents Chemother.2016 Nov 21;60(12):7086-7097.

Bictegravir is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxylic acid with the amino group of 2,4,6-trifluorobenzylamine. It is a second-generation integrase strand transfer inhibitor (INSTI) and used (as its sodium salt) for the treatment of HIV-1. It has a role as a HIV-1 integrase inhibitor. It is a monocarboxylic acid amide, a secondary carboxamide, a trifluorobenzene and an organic heterotetracyclic compound. It is a conjugate acid of a bictegravir(1-).
Bictegravir is a recently approved investigational drug that has been used in trials studying the treatment of HIV-1 and HIV-2 infection. It has been approved for HIV-1 monotherapy combined with 2 other antiretrovirals in a single tablet.
Bictegravir is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor, the fourth in this class of agents that target the viral integrase. Bictegravir is used only in combination with other antiretroviral agents in the treatment of HIV infection and it has had limited use. Bictegravir is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of acute, clinically apparent liver injury.
Bictegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), that is used to treat HIV infection. Upon oral administration, bictegravir inhibits the strand transfer activity of HIV-1 integrase, an HIV-1 coded enzyme that is necessary for viral replication. Inhibition of integrase prevents the integration of linear HIV-1 DNA into host genomic DNA.

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Drug Indication
Bictegravir is indicated in the management of HIV-1 infection in patients not previously treated with antiretroviral therapy. Additionally, Bictegravir is indicated in the management of HIV-1 infection in patients who are virologically suppressed (HIV-1 RNA <50 c/mL) on a regular antiretroviral regimen for a minimum of three months without a history of failure in treatment and no known factors associated with the resistance to the individual components of the medication. It is used in combination with tenofovir and emtricitabine.
FDA Label

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Mechanism of Action
This single dose medication inhibits the strand transfer of viral DNA into the human genome, preventing HIV-1 virus replication and propagation. In vitro, bictegravir has shown powerful antiviral activity against HIV-2 and various subtypes of HIV-1. It has shown synergistic effects when combined with other ARVs, including tenofovir alafenamide (TAF), emtricitabine (FTC), and darunavir (DRV). The three components of the first USA approved medication ( trade name: Biktarvy ) are as follows: Bictegravir: integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme necessary for viral replication. Inhibition of the integrase enzyme prevents the integration of HIV-1 into host DNA, blocking the conversion of the HIV-1 provirus and progression of the virus [FDA LABEL]. Emtricitabine: FTC, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine is phosphorylated to form emtricitabine 5'-triphosphate intracellularly. This metabolite inhibits the activity of human immunodeficiency virus (HIV) reverse transcriptase by competing with the substrate deoxycytidine 5'-triphosphate and by incorporating itself into viral DNA preventing DNA chain elongation [FDA LABEL]. Tenofovir Alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2′-deoxyadenosine monophosphate analog). Plasma exposure to TAF leads to leakage into cells and then TAF is intracellularly converted to tenofovir by hydrolysis by cathepsin. Tenofovir is subsequently phosphorylated by cellular kinases to the metabolite tenofovir diphosphate, which is the active form of the drug. Tenofovir diphosphate inhibits HIV-1 replication by incorporating into viral DNA by the HIV reverse transcriptase, resulting in DNA chain-termination. Tenofovir diphosphate also weakly inhibits mammalian DNA polymerases [FDA LABEL].

C21H18F3N3O5

449.37

449.119

C, 56.13; H, 4.04; F, 12.68; N, 9.35; O, 17.80

1611493-60-7

Bictegravir sodium;1807988-02-8;Bictegravir-15N,d2

90311989

Solid powder

1.62±0.1 g/cm3

682.5±55.0 °C at 760 mmHg

366.6±31.5 °C

0.0±2.2 mmHg at 25°C

1.664

-1.26

2

9

3

32

912

3

FC1C=C(C=C(C=1CNC(C1C(C(=C2C(N3[C@@H](CN2C=1)O[C@@H]1CC[C@H]3C1)=O)O)=O)=O)F)F

SOLUWJRYJLAZCX-LYOVBCGYSA-N

InChI=1S/C21H18F3N3O5/c22-9-3-14(23)12(15(24)4-9)6-25-20(30)13-7-26-8-16-27(10-1-2-11(5-10)32-16)21(31)17(26)19(29)18(13)28/h3-4,7,10-11,16,29H,1-2,5-6,8H2,(H,25,30)/t10-,11+,16+/m0/s1

(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO : 83.3 ~90 mg/mL ( 185.37 ~200.27 mM）

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.56 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.56 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: ≥ 2.5 mg/mL (5.56 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
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.

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Solubility in Formulation 5: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (5.56 mM)

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