title: In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450.
abstract: The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.).
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA tami.pilot-matias@abbvie.com.
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gaultier
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Dekhtyar
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Liangjun
authors.initials: L
authors.lastname: Lu
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reisch
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Irvin
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Hopkins
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Pithawalla
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Middleton
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ng
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: McDaniel
authors.affiliation: Enanta Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Yat Sun
authors.initials: YS
authors.lastname: Or
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Menon
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Kempf
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Collins
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D011392:Proline; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C585405:paritaprevir