glecaprevir

glecaprevir
IUPAC name	(1R,2S,5S)-N-[(1S,2R)-1-[(Cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl]-3-[(2S)-2-(5,6-dihydro-2-{2-[(methoxycarbonyl)amino]-4-(1-methylethyl)-1,3-thiazol-5-yl}-1H-cyclopenta[4,5]pyrrolo[1,2-b]pyridazin-1-yl)-5-azabicyclo[3.1.0]hex-2-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-4-carboxamide
Tradename	Mavyret, Maviret
CAS number	1365970-03-1
DrugBank	DB11960
UNII	1M6138T0M8
ATC prefix	J05
ATC suffix	AP57

glecaprevir is a direct-acting antiviral medication used in combination with pibrentasvir for the treatment of chronic hepatitis C virus infection. It is a potent inhibitor of the NS3/4A protease, a key enzyme essential for viral replication. The combination therapy, marketed as Mavyret, is indicated for all major genotypes of hepatitis C virus and is a cornerstone of modern curative regimens.

Medical uses

Glecaprevir is co-formulated with pibrentasvir and is indicated for the treatment of adult and pediatric patients with chronic hepatitis C virus infection across genotypes 1 through 6 without cirrhosis or with compensated cirrhosis. This regimen is also approved for patients with chronic kidney disease, including those on hemodialysis, and is a key option for those who have previously failed therapy with other direct-acting antiviral agents. The Food and Drug Administration and the European Medicines Agency have approved its use based on high sustained virologic response rates observed in clinical trials such as ENDURANCE and EXPEDITION.

Adverse effects

The most commonly reported adverse reactions in patients treated with the glecaprevir/pibrentasvir combination include headache, fatigue, and nausea. Serious adverse effects are rare but can include elevations in alanine aminotransferase and bilirubin levels, particularly in patients with severe hepatic impairment. The prescribing information includes a black box warning regarding the risk of hepatitis B virus reactivation in co-infected patients, a risk managed by the Centers for Disease Control and Prevention guidelines.

Pharmacology

Glecaprevir exerts its pharmacological effect by directly inhibiting the NS3/4A protease of the hepatitis C virus, thereby preventing the cleavage of the viral polyprotein and halting the assembly of functional viral replication complexes. Following oral administration, it is extensively metabolized in the liver primarily via CYP3A4 enzymes and is a substrate for drug transporters including P-glycoprotein. Its pharmacokinetic profile supports once-daily dosing, and it achieves high concentrations in hepatocytes, its primary site of action.

Chemistry

Glecaprevir is a macrocyclic peptidomimetic inhibitor with a complex molecular structure designed to fit precisely into the active site of the NS3/4A protease. It is a white to off-white powder that is practically insoluble in water. The chemical synthesis of glecaprevir involves multiple stereoselective steps to construct its characteristic bicyclic proline moiety and intricate macrocyclic core, a process developed by researchers at AbbVie.

History

The discovery and development of glecaprevir were led by scientists at AbbVie following the success of earlier protease inhibitors like boceprevir and telaprevir. Its clinical development program was accelerated after the breakthrough designation by the Food and Drug Administration. The glecaprevir/pibrentasvir combination received its first global approval in the United States in August 2017, marking a significant advancement in pan-genotypic therapy for hepatitis C.

Society and culture

The introduction of glecaprevir as part of a pan-genotypic regimen has had a profound impact on global efforts to eliminate hepatitis C, supported by initiatives from the World Health Organization. Its high efficacy and shorter treatment duration have influenced treatment guidelines worldwide, including those from the American Association for the Study of Liver Diseases. The drug is marketed under the trade names Mavyret in the U.S. and Maviret in the European Union.

Category:Antiviral drugs Category:Hepatitis C antiviral drugs Category:AbbVie