Daclatasvir

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.

Based on animal models, daclatasvir is not shown to cause adverse events at levels used in humans; however, combination therapy with ribavirin is contraindicated in pregnant women and male partners of pregnant women. It is not known whether daclatasvir passes into breastmilk or has any effect on infants. Breastfeeding is safe and does not transmit HCV, however, the CDC recommends avoiding breastfeeding if the infected mother's nipples are cracked or bleeding.

Interactions and contraindications

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 daclatascir 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.

Adverse effects

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 >10% 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.

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.