title: Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: safety, antiviral activity, resistance, and pharmacokinetics.
abstract: Vaniprevir is a competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease that has potent anti-HCV activity in preclinical models. This placebo-controlled dose-ranging study assessed the safety, tolerability, and antiviral efficacy of vaniprevir monotherapy in patients with genotype 1 chronic HCV infection. Treatment-naive and treatment-experienced non-cirrhotic adult patients with baseline HCV RNA >10(6)IU/ml were randomized to receive placebo or vaniprevir at doses of 125 mg qd, 600 mg qd, 25mg bid, 75 mg bid, 250 mg bid, 500 mg bid, and 700 mg bid for 8 days. Forty patients (82.5% male, 75% genotype 1a) received at least one dose of placebo or vaniprevir. After 1 week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6 log₁₀IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75 mg bid. The most commonly reported drug-related adverse events (AEs) were diarrhea (n=5) and nausea (n=5). No pattern of laboratory or ECG abnormalities was observed, all AEs resolved during the study, and there were no discontinuations due to AEs. No serious AEs were reported. Resistance-associated amino acid variants were identified at positions R155 and D168 in patients infected with genotype 1a virus. Vaniprevir monotherapy demonstrated potent antiviral activity in patients with chronic genotype 1 HCV infection, and was generally well tolerated with no serious AEs or discontinuations due to AEs. Further development of vaniprevir, including studies in combination with other anti-HCV agents, is ongoing.
authors.affiliation: Alamo Medical Research, 621 Camden Street, San Antonio, TX 78215, United States. Electronic address: lawitz@alamomedicalresearch.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Mark
authors.initials: M
authors.lastname: Sulkowski
authors.forename: Ira
authors.initials: I
authors.lastname: Jacobson
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kraft
authors.forename: Benedict
authors.initials: B
authors.lastname: Maliakkal
authors.forename: Mohamed
authors.initials: M
authors.lastname: Al-Ibrahim
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Gordon
authors.forename: Paul
authors.initials: P
authors.lastname: Kwo
authors.forename: Juergen Kurt
authors.initials: JK
authors.lastname: Rockstroh
authors.forename: Paul
authors.initials: P
authors.lastname: Panorchan
authors.forename: Michelle
authors.initials: M
authors.lastname: Miller
authors.forename: Luzelena
authors.initials: L
authors.lastname: Caro
authors.forename: Richard
authors.initials: R
authors.lastname: Barnard
authors.forename: Peggy May
authors.initials: PM
authors.lastname: Hwang
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gress
authors.forename: Erin
authors.initials: E
authors.lastname: Quirk
authors.forename: Niloufar
authors.initials: N
authors.lastname: Mobashery
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D047908:Intracellular Signaling Peptides and Proteins; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D003521:Cyclopropanes; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine; D011392:Proline; D011480:Protease Inhibitors; 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; C455041:NS4A cofactor peptide, Hepatitis C virus; C540393:vaniprevir
keywords: AE; AUC; BMI; BUN; C(max); C(trough); CI; CRU; DAA; Dose-ranging; EC(50); ECG; Efficacy; GMR; GT; HCV; IC(50); IRF-3; LLoQ; MRL; Merck Research Laboratories; Monotherapy; NS3/4A; PCR; PD; PEG-IFN; PI; PK; Pharmacokinetics; RAVs; RBV; SAE; SEAP; SVR; Safety; T(max); ULN; adverse event; area under the concentration-time curve; bid; blood urea nitrogen; body mass index; clinical research unit; confidence interval; direct-acting antiviral; electrocardiogram; genotype; geometric mean ratio; half-maximal effective concentration; half-maximal inhibitory concentration; hepatitis C virus; interferon regulatory factor 3; lower limit of quantitation; maximum concentration; maximum time to reach C(max); nonstructural protein 3/4A; once daily; pegylated interferon; pharmacodynamic(s); pharmacokinetic(s); polymerase chain reaction; protease inhibitor; qd; resistance-associated amino acid variants; ribavirin; secreted alkaline phosphatase; serious adverse event; sustained viral response; t(1/2); terminal half-life; trough concentration; twice daily; upper limit of normal