Velpatasvir is an NS5A inhibitor (by

Gilead Gilead or Gilad (; he, גִּלְעָד ''Gīləʿāḏ'', ar, جلعاد, Ǧalʻād, Jalaad) is the ancient, historic, biblical name of the mountainous northern part of the region of Transjordan.''Easton's Bible Dictionary'Galeed''/ref> ...

) which is used together with

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 i ...

in the treatment of

hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, ...

infection of all six major genotypes.

Side effects

Side effects in studies occurred with similar frequencies as in people treated with

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

Interactions

Velpatasvir is both an inhibitor and a substrate of the transporter proteins

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

(Pgp),

ABCG2 ATP-binding cassette super-family G member 2 is a protein that in humans is encoded by the ''ABCG2'' gene. ABCG2 has also been designated as CDw338 (cluster of differentiation w338). ABCG2 is a translocation protein used to actively pump drugs ...

, OATP1B1 and OATP1B3. It is partly degraded by the liver enzymes

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Func ...

CYP2C8 Cytochrome P4502C8 (abbreviated CYP2C8), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-cha ...

and

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

. Substances that are transported or inactivated by these proteins, or interfere with them, can interact with velpatasvir. In studies, this has been found for the HIV combination

efavirenz/emtricitabine/tenofovir Efavirenz/emtricitabine/tenofovir, sold under the brand name Atripla among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains efavirenz, emtricitabine, and tenofovir disoproxil. It can be used ...

, which reduces the

area under the curve In mathematics, an integral assigns numbers to functions in a way that describes displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding integrals is called integration. Along with ...

(AUC) of velpatasvir by about 50%, and the CYP3A4 and Pgp inducer

rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. It is almost always used t ...

, which reduces its AUC by about 80%, rendering it likely ineffective.

Digoxin Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is o ...

is eliminated by Pgp; its AUC is increased by about 30% in combination with velpatasvir and sofosbuvir (although it is not clear which of the two is responsible for this effect). Substances that reduce gastric acid, such as

antacid An antacid is a substance which neutralizes stomach acidity and is used to relieve heartburn, indigestion or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhea. Marketed antacids contain salts of alu ...

s, H₂ blockers, and

proton pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...

s, reduce velpatasvir AUC by 20–40%.

Pharmacology

Mechanism of action

The substance blocks

NS5A Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without ''trans''-membrane helices. Structure NS5A is deri ...

, a protein necessary for hepatitis C virus replication and assembly.

Pharmacokinetics

Velpatasvir reaches highest blood plasma levels three hours after oral intake together with sofosbuvir. Plasma protein binding is over 99.5%. It is slowly metabolised by the liver enzymes CYP2B6, CYP2C8 and CYP3A4. While mono hydroxylated and demethylated metabolites have been identified in human blood plasma and faeces, over 98% of the circulating substance is velpatasvir itself. 94% are excreted via the faeces, and only 0.4% via the urine.

Biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

is about 15 hours.

References