Daclatasvir

{{Infobox drug
| drug_name = 
| type =
| IUPAC_name =  Dimethyl N,''N-([1,1'-biphenyl]-4,4'-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-diyl][(2S)-3-methyl-1-oxobutane-1,2-diyl]})dicarbamate
| image = Daclatasvir.svg
| width = 275
| alt =
| caption =

| pronounce = 
| tradename = Daklinza
| Drugs.com = 
| MedlinePlus = a615044
| pregnancy_AU = 
| pregnancy_AU_comment = 
| pregnancy_US = 
| pregnancy_category =
| routes_of_administration = By mouth (tablets)
| licence_EU = yes
| legal_AU = 
| legal_AU_comment =
| legal_CA = Rx-only
| legal_DE = 
| legal_NZ = 
| legal_UK = 
| legal_US = Rx-only
| legal_UN = 
| legal_status = Rx-only

| bioavailability = 67%
| protein_bound = 99%
| metabolism = CYP3A
| metabolites =
| onset =
| elimination_half-life = 12–15 hours
| duration_of_action =
| excretion = Fecal (53% as unchanged drug), kidney

| CAS_number = 1009119-64-5
| ATCvet =
| ATC_prefix = J05
| ATC_suffix = AP07
| PubChem = 25154714
| ChEBI = 82977
| ChemSpiderID = 24609522
| DrugBank = DB09102
| KEGG = D10065
| UNII = LI2427F9CI

| chemical_formula =
| C=40 | H=50 | N=8 | O=6
| molecular_weight = 738.89 g/mol
| smiles = CC(C)[C@@H](C(=O)N1CCC[C@H]1c2[nH]c(cn2)c3ccc(cc3)c4ccc(cc4)c5cnc([nH]5)[C@@H]6CCCN6C(=O)[C@H](C(C)C)NC(=O)OC)NC(=O)OC
| StdInChI=1S/C40H50N8O6/c1-23(2)33(45-39(51)53-5)37(49)47-19-7-9-31(47)35-41-21-29(43-35)27-15-11-25(12-16-27)26-13-17-28(18-14-26)30-22-42-36(44-30)32-10-8-20-48(32)38(50)34(24(3)4)46-40(52)54-6/h11-18,21-24,31-34H,7-10,19-20H2,1-6H3,(H,41,43)(H,42,44)(H,45,51)(H,46,52)/t31-,32-,33-,34-/m0/s1
| StdInChIKey = FKRSSPOQAMALKA-CUPIEXAXSA-N
}}Daclatasvir, sold under the trade name Daklinza''', is a medication used in combination with other medications to treat hepatitis C (HCV).  The other medications used in combination include sofosbuvir, ribavirin, and interferon, vary depending on the virus type and whether the person has cirrhosis.  It is taken by mouth once a day. 

Common side effects with sofusbivir and daclatasvir include headache, feeling tired, and nausea.  With daclatasvir, sofusbivir, and ribavirin the most common side effects are headache, feeling tired, nausea, and red blood cell breakdown.  It should not be used with St. John's wort, rifampin, or carbamazepine.  It works by inhibiting the HCV protein NS5A.

Daclatasvir was approved for use in Europe in 2014 and the United States and India in 2015.  It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.  As of January 2016 a twelve-week course cost around $63,000 in the United States, $39,000 in the United Kingdom, $37,000 in France, and $525 in Egypt. 

Medical use 
Daclatasvir is used only in combination therapy for the treatment of hepatitis C genotype 1, 3, or 4 infections; the agents used in combination, which include sofosbuvir, ribavirin, and interferon, vary based on the virus genotype and whether the person has cirrhosis. 

It is not known whether daclatasvir passes into breastmilk or has any effect on infants. 

Adverse effects 
There is a serious risk of bradycardia when daclatasvir is used with sofosbuvir and amiodarone

Because it has not been extensively studied as a single agent, it is unknown what specific side effects are linked to this medication alone.  Adverse events on daclatasvir have only been reported on combination therapy with sofusbivir or triple therapy with sofusbivir/ribavirin. 

Common adverse events occurring in >5% of people on combination therapy (sofusbivir + daclatasvir) include headache and fatigue; in triple therapy (daclatasvir + sofusbivir + ribavirin) the most common adverse events (>10%) include headache, fatigue, nausea and hemolytic anemia. 

Daclatasvir could cause hepatitis B re-activation in people co-infected with hepatitis B and C viruses.  The European Medicines Agency (EMA) has recommended screening all people for hepatitis B before starting daclatasvir for hepatitis C in order to minimize the risk of hepatitis B reactivation. 

Interactions 
Concomitant use of drugs that are strong inducers of the cytochrome P450 CYP3A is contraindicated due to decreased therapeutic effect and resistance of drug.   Some common drugs that are strong CYP3A inducers include dexamethasone, phenytoin, carbamazepine, rifampin and St. John's Wort. 

Daclatasvir is a CYP3A and p-glycoprotein substrate, therefore, drugs that are strong inducers or inhibitors of these enzyme will interfere with daclatasvir levels in the body.  Dose modifications are made with concomitant use of daclatasvir and drugs that affect CYP3A or p-gp.  When taking daclatasvir with non-nucleoside reverse transcriptase inhibitors, the dose of daclatasvir is increased to overcome CYP3A induction.  The dose for daclatasvir should be lowered when taking with antifungals, such as ketoconazole.  Currently, there are no required dosage adjustments with concurrent use of daclatasvir and immunosuppressants, narcotic analgesics, antidepressants, sedatives, and cardiovascular agents. 

Concurrent use with amiodarone, sofosbuvir and daclatasvir has may result in an increased risk for serious slowing of the heart rate. 

Pharmacology

Mechanism of action 
Daclatasvir stops HCV viral RNA replication and protein translation by directly inhibiting HCV protein NS5A.  NS5A is critical for HCV viral transcription and translation, and as of 2014 it appeared that resistance can arise to daclatasvir fairly swiftly. 

Pharmacokinetics 
Daclatasvir reaches steady state in human subjects after about 4 days of once-daily 60 mg oral administration, with a peak dose in concentration occurring about 2 hours after administration.   It comes in the form of an oral tablet, with a bioavailability of 67%.  Daclatasvir is predominantly metabolized by the liver enzyme CYP3A4, and is also a P-gp substrate.  It is highly protein bound.  Protein binding was measured to be around 99% in people dosed multiple times with daclatasvir independent of dose strength.  Daclatasvir has a volume of distribution of 47L following an oral dose of 60 mg and an IV dose of 100 μg. 

History

Daklinza was discovered by scientists at Bristol-Myers Squibb (BMS); the precursor was identified using phenotypic screening in which the GT-1b replicon system was implemented in Huh7 cells and bovine viral diarrhea virus also in Huh7 cells was used as a counterscreen for specificity.   BMS also developed the drug, with the first Phase I trial publishing in 2010. 

It was approved for use in Europe in August 2014, in the US in July 2015, and in India in December 2015; it was first in the class of NS5A inhibitors to reach the market. 

Society and culture
It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system. 

In December 2014 BMS announced that it would offer the drug for sale at different prices in different countries, depending on the level of economic development, and that it would license the drug to generics manufacturers for sale in the developing world. 

As of January 2016 a twelve-week course cost around $63,000 in the US, around $39,000 in the UK, around $37,000 in France, and $525 in Egypt, and by that time BMS had joined the Medicines Patent Pool. 

Research
Daclatasvir has been tested in combination regimens with pegylated interferon and ribavirin, as well as with other direct-acting antiviral agents including asunaprevir and sofosbuvir. 

References

Category:NS5A inhibitors
Category:Carbamates
Category:Imidazoles
Category:Pyrrolidines
Category:Biphenyls
Category:World Health Organization essential medicines
Category:RTT