HCV genotype 1b N(IC50=2.2 ± 0.3 nM);HCV genotype 1a H77(IC50=2.8 ± 0.2 nM);HCV genotype 1b BK(IC50=3.1 ± 0.21 nM);HCV genotype 1b Con1(IC50=0.7 ± 1.4 nM)

Dasabuvir is at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. Dasabuvir inhibits the polymerase enzymatic activity of genotype 1 laboratory strain enzymes (H77, BK, N, and Con1 strains), as well as enzymes produced from polymerase genes from HCV genotype 1-infected subjects, with IC50s between 2.2 and 10.7 nM. Dasabuvir inhibits replication of HCV subgenomic replicons in cell culture assays, with EC50 values of 7.7 and 1.8 nM against genotype 1a (H77) and 1b (Con1), respectively. In the presence of 40% human plasma, there is a 12- to 13-fold decrease in inhibitory potency, yielding EC50s of 99 and 21 nM for HCV genotype 1a (H77) and 1b (Con1) replicons, respectively.

the inhibition of human and mammalian DNA polymerases was evaluated by Replizyme Ltd. (Heslington, United Kingdom). The DNA-dependent RNA polymerase activity for human RNA polymerases II and III was measured using polymerases present in a HeLa cell extract and DNA templates containing promoters specific for either polymerase II or polymerase III. α-Amanitin, a potent inhibitor of human polymerase II and a modest inhibitor of polymerase III, was used as a control. The reaction mixtures contained 20 mM Tris-HCl (pH 8.0), 20% glycerol, 100 mM KCl, 1 mM dithiothreitol (DTT), 0.2 mM EDTA, 6 mM MgCl2, and either 1 μg/μl pAdVAntage plasmid (Promega, Madison, WI) (for the polymerase III assay) or 25 ng/μl cytomegalovirus (CMV) promoter DNA (Promega, Madison, WI) (for the polymerase II assay). The reaction mixtures also contained HeLa cell nuclear extract (ProteinOne, Rockville, MD), 400 μM ATP, CTP, and UTP, and 16 μM GTP and [α-33P]GTP. The reaction mixtures were incubated for 1 h at 30°C, quenched with the addition of proteinase K, SDS, and EDTA, incubated for 30 min at 56°C, and then analyzed on a Criterion Bio-Rad 5% acrylamide Tris-borate-EDTA (TBE)-urea gel. The gel was dried and placed on a PhosphorImager screen for overnight exposure. The volumes of the product bands were measured, and the percent inhibition was calculated; IC50 values were calculated using the following equation: % inhibition = 100[I]/([I] + IC50).

Dasabuvir (ABT-333) is at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. Dasabuvir (ABT-333) inhibits the polymerase enzymatic activity of genotype 1 laboratory strain enzymes (H77, BK, N, and Con1 strains), as well as enzymes produced from polymerase genes from HCV genotype 1-infected subjects, with IC50s between 2.2 and 10.7 nM. Dasabuvir (ABT-333) inhibits replication of HCV subgenomic replicons in cell culture assays, with EC50 values of 7.7 and 1.8 nM against genotype 1a (H77) and 1b (Con1), respectively. In the presence of 40% human plasma, there is a 12- to 13-fold decrease in inhibitory potency, yielding EC50s of 99 and 21 nM for HCV genotype 1a (H77) and 1b (Con1) replicons, respectively.

Absorption, Distribution and Excretion
Dasabuvir reaches peak plasma concentration 4 hours after administration. The absolute bioavailability of Dasabuvir is 70%.
Dasabuvir is mainly excreted in the feces (94.4%) with very little excreted in the urine (2%). 26.2% and 0.03% of the drug excreted in the feces and urine respectively was present as the parent compound suggesting metabolism as the major elimination pathway.
Dasabuvir has a volume of distribution at steady state of 149 liters.
Clearance of Dasabuvir has not been determined.

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Metabolism / Metabolites
Dasabuvir is predominantly metabolized by CYP2C8, and to a lesser extent by CYP3A.

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Biological Half-Life
The half-life of elimination of dasabuvir is 5.5 to 6 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Dasabuvir has not been studied in nursing mothers being treated for hepatitis C infection. Because it is greater than 99.5% bound to maternal plasma proteins, amounts in breastmilk are likely to be very low. If dasabuvir used alone or in combination with sofosbuvir or with ombitasvir, paritaprevir and ritonavir (Viekira Pak) is required by the mother, it is not a reason to discontinue breastfeeding. Some sources recommend against breastfeeding when dasabuvir is used with ribavirin.
Ritonavir used as a booster has been studied in several studies of breastfeeding mothers. It is excreted into milk in measurable concentrations and low levels can be found in the blood of some breastfed infants. No reports of adverse reactions in breastfed infants have been reported. For more information, refer to the LactMed record on ritonavir.
Hepatitis C is not transmitted through breastmilk and breastmilk has been shown to inactivate hepatitis C virus (HCV). However, the Centers for Disease Control recommends that mothers with HCV infection should consider abstaining from breastfeeding if their nipples are cracked or bleeding. It is not clear if this warning would apply to mothers who are being treated for hepatitis C.
Infants born to mothers with HCV infection should be tested for HCV infection; because maternal antibody is present for the first 18 months of life and before the infant mounts an immunologic response, nucleic acid testing is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Dasabuvir is greater than 99.5% bound to human plasma proteins.

[1]. In vitro activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitor. Antimicrob Agents Chemother. 2015 Mar;59(3):1505-11.

Dasabuvir is a member of the class of pyrimidone, which is (as the monohydrate of its sodium salt) in combination with ombitasvir, paritaprevir and ritonavir (under the trade name Viekira Pak) for treatment of chronic hepatitis C virus genotype 1 infection as well as cirrhosis of the liver. It has a role as an antiviral drug and a nonnucleoside hepatitis C virus polymerase inhibitor. It is a member of naphthalenes, a sulfonamide, an aromatic ether and a pyrimidone. It is functionally related to a uracil.
Dasabuvir is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as Dasabuvir. Dasabuvir is a non-nucleoside NS5B inhibitor which binds to the palm domain of NS5B and induces a conformational change which renders the polymerase unable to elongate viral RNA. The binding sites for non-nucleoside NS5B inhibitors are poorly conserved across HCV genotypes leading to the restriction of Dasabuvir's use to genotype 1 only. In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Dasabuvir as first line therapy in combination with [DB09296], [DB09297], and [DB00503] for genotype 1b and with [DB00811] for genotype 1a of Hepatitis C. Dasabuvir, [DB09296], [DB09297], [DB00503], and [DB00811] are used with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality. Dasabuvir is available as a fixed dose combination product with [DB09296], [DB09297], and [DB00503] (tradename Viekira Pak) used for the treatment of chronic Hepatitis C. Approved in December 2014 by the FDA, Viekira Pak is indicated for the treatment of HCV genotype 1a with [DB00811] or genotype 1b without [DB00811]. When combined together, Dasabuvir [DB09296], [DB09297], and [DB00503] as the combination product Viekira Pak have been shown to achieve a SVR of 100% for genotype 1b and 89% or 95% for genotype 1a after 12 weeks or 24 weeks of treatment including [DB00811].
Dasabuvir is a Hepatitis C Virus Non-Nucleoside NS5B Palm Polymerase Inhibitor. The mechanism of action of dasabuvir is as a RNA Replicase Inhibitor, and UGT1A1 Inhibitor, and Breast Cancer Resistance Protein Inhibitor.
Dasabuvir is a non-nucleoside inhibitor of the hepatitis C virus (HCV) non-structural protein 5B (NS5B), an RNA-dependent RNA polymerase, with potential activity against HCV. Upon administration and after intracellular uptake, dasabuvir binds HCV NS5B polymerase and blocks viral RNA synthesis and replication. The HCV NS5B protein is essential for the replication of the HCV RNA genome. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family; HCV infection is associated with the development of hepatocellular carcinoma (HCC).

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Drug Indication
Dasabuvir, in combination with [DB09296], [DB09297], and [DB00503] (as Viekira Pak) is indicated for the treatment of patients with HCV genotype 1a with [DB00811] or genotype 1b without [DB00811] including those with compensated cirrhosis.
FDA Label
Exviera is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults. For hepatitis C virus (HCV) genotype specific activity.

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Mechanism of Action
Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. Based on drug resistance mapping studies of HCV genotypes 1a and 1b, dasabuvir targets the palm domain of the NS5B polymerase, and is therefore referred to as a non-nucleoside NS5B-palm polymerase inhibitor. The EC50 values of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays were 7.7 nM and 1.8 nM, respectively. By binding to NS5b outside of the active site of the enzyme, dasabuvir induces a conformational change thereby preventing further elongation of the nascent viral genome. A limitation of binding outside of the active site is that these binding sites are poorly preserved across the viral genotypes. This results in a limited potential for cross-genotypic activity and increased potential for development of resistance. Dasabuvir is therefore limited to treating genotypes 1a and 1b, and must be used in combination with other antiviral products.

C26H27N3O5S

493.57

493.167

C, 63.27; H, 5.51; N, 8.51; O, 16.21; S, 6.50

1132935-63-7

Dasabuvir sodium;1132940-11-4

56640146

White to off-white solid powder.

1.3±0.1 g/cm3

1.641

3.68

2

6

6

35

938

0

S(C([H])([H])[H])(N([H])C1C([H])=C([H])C2=C(C=1[H])C([H])=C([H])C(=C2[H])C1C([H])=C(C([H])=C(C=1OC([H])([H])[H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])N1C([H])=C([H])C(N([H])C1=O)=O)(=O)=O

NBRBXGKOEOGLOI-UHFFFAOYSA-N

InChI=1S/C26H27N3O5S/c1-26(2,3)22-15-20(29-11-10-23(30)27-25(29)31)14-21(24(22)34-4)18-7-6-17-13-19(28-35(5,32)33)9-8-16(17)12-18/h6-15,28H,1-5H3,(H,27,30,31)

N-(6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

ABT333; ABT-333; ABT 333, Dasabuvir; Trade names: Viekira Pak

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)

DMSO : 46~98 mg/mL ( 93.20 ~198.55 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.07 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 (5.07 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 (5.07 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: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (5.07 mM)

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