pibrentasvir

pibrentasvir
IUPAC name	Methyl (2S,3S,5R)-3-({6-{5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino}-2-azabicyclo[3.3.0]octan-3-yl)carbamate
Width	200
CAS number	1353900-92-1
PubChem	67524336
DrugBank	DB11999
UNII	2WQ0K7QJ6I
Synonyms	ABT-530

pibrentasvir is a direct-acting antiviral medication used in combination with other agents for the treatment of chronic hepatitis C virus infection. It functions as a potent inhibitor of the viral NS5A protein, a critical component for viral replication and assembly. Developed by AbbVie, it is a key component of the pan-genotypic regimen glecaprevir/pibrentasvir, marketed as Mavyret. This combination therapy has significantly advanced the management of hepatitis C by offering a high cure rate across all major HCV genotypes with a shortened treatment duration.

Medical uses

Pibrentasvir is co-formulated with glecaprevir for the treatment of adult and pediatric patients with chronic hepatitis C virus infection across all six major genotypes. This regimen is indicated for patients without cirrhosis or with compensated cirrhosis, including those who have previously failed therapy with an NS5A inhibitor or an NS3/4A protease inhibitor. Clinical trials, such as those conducted at the University of Texas Southwestern Medical Center and published in journals like The New England Journal of Medicine, demonstrated sustained virologic response rates exceeding 95% in diverse patient populations. It is also approved for use in patients with severe renal impairment and those on hemodialysis, a population historically difficult to treat.

Adverse effects

The most commonly reported adverse reactions for the glecaprevir/pibrentasvir combination are generally mild and include headache, fatigue, and nausea. Serious adverse events are rare but can include elevations in alanine aminotransferase and significant hyperbilirubinemia. Due to the glecaprevir component, there is a risk of hepatotoxicity, and its use is contraindicated in patients with moderate or severe hepatic impairment. Post-marketing surveillance coordinated by agencies like the U.S. Food and Drug Administration and the European Medicines Agency continues to monitor the safety profile.

Pharmacology

Pibrentasvir exerts its antiviral effect by binding to the N-terminal domain of the HCV NS5A protein, a multifunctional phosphoprotein essential for viral RNA replication and the assembly of new virions. Its mechanism involves disrupting the formation of the viral replication complex and interfering with hyperphosphorylation. Pharmacokinetic studies show it is primarily metabolized by CYP3A4 and is a substrate for the drug transporters P-glycoprotein and BCRP. The combination with glecaprevir enhances antiviral potency and presents a high barrier to resistance, effectively suppressing variants with substitutions at key positions like Y93H.

Chemistry

Pibrentasvir is a complex macrocyclic molecule belonging to the chemical class of NS5A inhibitors. Its structure features a unique proline-methylimidazole-pyrrolopyrimidine core designed to optimize binding to the NS5A dimer. The synthesis, pioneered by researchers at AbbVie and detailed in publications such as the Journal of Medicinal Chemistry, involves a convergent strategy to construct the challenging pentacyclic scaffold. The final drug substance is formulated as a co-packaged tablet with glecaprevir, utilizing pharmaceutical excipients to ensure stability and bioavailability.

History

The discovery and development of pibrentasvir originated from research programs at Abbott Laboratories, which later became AbbVie. It was designed as a next-generation NS5A inhibitor to overcome limitations of earlier agents like daclatasvir and ledipasvir, particularly against non-genotype 1 viruses and resistant variants. The phase III clinical trial program, ENDURANCE, demonstrated its pan-genotypic efficacy. Regulatory approval from the U.S. Food and Drug Administration and the European Commission for glecaprevir/pibrentasvir was granted in 2017, following priority review designations.

Society and culture

The introduction of glecaprevir/pibrentasvir had a substantial impact on global hepatitis C elimination efforts advocated by the World Health Organization. Its shorter, 8-week duration for most patients and pan-genotypic activity addressed key barriers to treatment access and cost. The drug's development and pricing have been subjects of discussion within health systems like the National Health Service in the United Kingdom and by payers in the United States. AbbVie has engaged in access agreements with several countries and organizations, including the Center for Disease Control and Prevention, to facilitate broader distribution.

Category:Antiviral drugs Category:Hepatitis C