Sofosbuvir
Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.
Common side effects include fatigue, headache, nausea, and trouble sleeping. Side effects are generally more common in interferon-containing regimens. Sofosbuvir may reactivate hepatitis B in those who have been previously infected. In combination with ledipasvir, daclatasvir or simeprevir, it is not recommended with amiodarone due to the risk of an abnormally slow heartbeat. Sofosbuvir is in the nucleotide analog family of medications and works by blocking the hepatitis C NS5B protein.
Sofosbuvir was discovered in 2007 and approved for medical use in the United States in 2013. It is on the World Health Organization's List of Essential Medicines.
Medical uses
Initial HCV treatment
In 2016, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America jointly published a recommendation for the management of hepatitis C. In this recommendation, sofosbuvir used in combination with other drugs is part of all first-line treatments for HCV genotypes 1, 2, 3, 4, 5, and 6, and is also part of some second-line treatments. Sofosbuvir in combination with velpatasvir is recommended for all genotypes with a cure rate greater than 90%, and close to 100% in most cases. The duration of treatment is typically 12 weeks.Sofosbuvir is also used with other medications and longer treatment durations, depending on specific circumstances, genotype and cost-effectiveness–based perspective. For example, for the treatment of genotypes 1, 4, 5, and 6 hepatitis C infections, sofosbuvir can be used in combination with the viral NS5A inhibitor ledipasvir. In genotype 2 and 3 HCV infections, sofosbuvir can be used in combination with daclatasvir. For the treatment of cases with cirrhosis or liver transplant patients, weight-based ribavirin is sometimes added. Peginterferon with or without sofosbuvir is not recommended in an initial HCV treatment.
Compared to previous treatments, sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a two- to four-fold reduction in therapy duration. Sofosbuvir allows most people to be treated successfully without the use of peginterferon, an injectable drug with severe side effects that is a key component of older drug combinations for the treatment of hepatitis C virus.
Prior failed treatment
For people who have experienced treatment failure with some form of combination therapy for hepatitis C infection, one of the next possible steps would be retreatment with sofosbuvir and either ledipasvir or daclatasvir, with or without weight-based ribavirin. The genotype and particular combination therapy a person was on when the initial treatment failed are also taken into consideration when deciding which combination to use next. The duration of retreatment can range from 12 weeks to 24 weeks depending on several factors, including which medications are used for the retreatment, whether the person has liver cirrhosis or not, and whether the liver damage is classified as compensated cirrhosis or decompensated cirrhosis.Pregnancy and breastfeeding
No adequate human data are available to establish whether or not sofosbuvir poses a risk to pregnancy outcomes. However, ribavirin, a medication that is often given together with sofosbuvir to treat hepatitis C, is assigned a Pregnancy Category X by the FDA. Pregnant women with hepatitis C who take ribavirin have shown some cases of birth defects and death in their fetus. It is recommended that sofosbuvir/ribarivin combinations be avoided in pregnant females and their male sexual partners in order to reduce harmful fetal defects caused by ribavirin. Females who could potentially become pregnant should undergo a pregnancy test 2 months prior to starting the sofosbuvir/ribavirin/peginterferon combination treatment, monthly throughout the duration of the treatment, and six months post-treatment to reduce the risk of fetal harm in case of accidental pregnancy.It is unknown whether sofosbuvir and ribavirin pass into breastmilk; therefore, it is recommended that the mother does not breastfeed during treatment with sofosbuvir alone or in combination with ribavirin.
Contraindications
There are no specific contraindications for sofosbuvir when used alone. However, when used in combination with ribavirin or peginterferon alfa/ribavirin, or others, the contraindications applicable to these agents are applied.Side effects
Sofosbuvir used alone and in combination with other drugs such as ribavirin with or without a peginterferon has a good safety profile. Common side effects are fatigue, headache, nausea, rash, irritability, dizziness, back pain, and anemia. Most side effects are more common in interferon-containing regimens as compared to interferon-free regimens. For example, fatigue and headache are nearly reduced by half, influenza-like symptoms are reduced to 3–6% as compared to 16–18%, and neutropenia is almost absent in interferon-free treatment.Sofosbuvir may reactivate hepatitis B in those who have been previously infected. The European Medicines Agency has recommended screening all people for hepatitis B before starting sofosbuvir for hepatitis C in order to minimize the risk of hepatitis B reactivation.
Interactions
Sofosbuvir should not be used with amiodarone due to the risk of abnormally slow heartbeats.Sofosbuvir is a substrate of P-glycoprotein, a transporter protein that pumps drugs and other substances from intestinal epithelium cells back into the gut. Therefore, inducers of intestinal P-glycoprotein, such as rifampicin and St. John's wort, could reduce the absorption of sofosbuvir.
In addition, coadministration of sofosbuvir with anticonvulsants, antimycobacterials, and the HIV protease inhibitor tipranavir and ritonavir is expected to decrease sofosbuvir concentration. Thus, coadministration is not recommended.
The interaction between sofosbuvir and a number of other drugs, such as ciclosporin, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil, were evaluated in clinical trials and no dose adjustment is needed for any of these drugs.
Pharmacology
Mechanism of action
Sofosbuvir inhibits the hepatitis C NS5B protein. Sofosbuvir appears to have a high barrier to the development of resistance.Sofosbuvir is a prodrug of the Protide type, whereby the active phosphorylated nucleotide is granted cell permeability and oral bioavailability. It is metabolized to the active antiviral agent GS-461203. GS-461203 serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, thus acts as an inhibitor of viral RNA synthesis. Although sofosbuvir has a 3' hydroxyl group to act as a nucleophile for an incoming NTP, a similar nucleotide analogue, 2'-deoxy-2'-α-fluoro-β-C-methylcytidine, is proposed to act as a chain terminator because the 2' methyl group of the nucleotide analogue causes a steric clash with an incoming NTP. Sofosbuvir may act in a similar way.
Pharmacokinetics
Sofosbuvir is only administered orally. The peak concentration after oral administration is 0.5–2 hours post-dose, regardless of initial dose. Peak plasma concentration of the main circulating metabolite GS-331077 occurs 2–4 hours post-dose. GS-331077 is the pharmacologically inactive nucleoside.Plasma protein binding of sofosbuvir is 61–65%, while GS-331077 has minimal binding.
Sofosbuvir is activated in the liver to the triphosphate GS-461203 by hydrolysis of the carboxylate ester by either of the enzymes cathepsin A or carboxylesterase 1, followed by cleaving of the phosphoramidate by the enzyme histidine triad nucleotide-binding protein 1, and subsequent repeated phosphorylation. Dephosphorylation creates the inactive metabolite GS-331077. The half life of sofosbuvir is 0.4 hours, and the half life of GS-331077 is 27 hours.Following a single 400 mg oral dose of sofosbuvir, 80% is excreted in urine, 14% in feces, and 2.5% in expired air recovery. However, of the urine recovery 78% was the metabolite and 3.5% was sofosbuvir.
Chemistry
Prior to the discovery of sofosbuvir, a variety of nucleoside analogs had been examined as antihepatitis C treatments, but these exhibited relatively low potency. This low potency arose in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. The design of sofosbuvir, based on the ProTide approach, avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell. The NS5B protein is a RNA-dependent RNA polymerase critical for the viral reproduction cycle.History
Sofosbuvir was discovered in 2007 by Michael J. Sofia, a scientist at Pharmasset, and the drug was first tested in people in 2010. In 2011, Gilead Sciences bought Pharmasset for about $11 billion. Gilead submitted the New Drug Application for sofosbuvir in combination with ribavirin in April 2013, and in October 2013 it received the FDA's Breakthrough Therapy Designation. In December 2013, the FDA approved sofosbuvir in combination with ribavirin for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon and RBV for treatment-naive people with HCV genotypes 1 and 4. Two months before, the FDA had approved another drug, simeprevir, as a hepatitis C treatment.In 2014, the fixed dose combination drug sofosbuvir/ledipasvir, the latter a viral NS5A inhibitor, was approved; it had also been granted breakthrough status.
Prior to the availability of sofosbuvir, hepatitis C treatments involved 6 to 12 months of treatment with an interferon-based regimen. This regimen provided cure rates of 70% or less and was associated with severe side effects, including anemia, depression, severe rash, nausea, diarrhea, and fatigue. As sofosbuvir clinical development progressed, physicians began to "warehouse" people in anticipation of its availability. Sofosbuvir's U.S. launch was the fastest of any new drug in history.