PMID- 23747481 OWN - NLM STAT- MEDLINE DCOM- 20140430 LR - 20211203 IS - 1872-9096 (Electronic) IS - 0166-3542 (Linking) VI - 99 IP - 3 DP - 2013 Sep TI - Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: safety, antiviral activity, resistance, and pharmacokinetics. PG - 214-20 LID - S0166-3542(13)00155-1 [pii] LID - 10.1016/j.antiviral.2013.05.015 [doi] AB - 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 log(1)(0)IU/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. CI - Copyright (c) 2013 Elsevier B.V. All rights reserved. FAU - Lawitz, Eric AU - Lawitz E AD - Alamo Medical Research, 621 Camden Street, San Antonio, TX 78215, United States. Electronic address: lawitz@alamomedicalresearch.com. FAU - Sulkowski, Mark AU - Sulkowski M FAU - Jacobson, Ira AU - Jacobson I FAU - Kraft, Walter K AU - Kraft WK FAU - Maliakkal, Benedict AU - Maliakkal B FAU - Al-Ibrahim, Mohamed AU - Al-Ibrahim M FAU - Gordon, Stuart C AU - Gordon SC FAU - Kwo, Paul AU - Kwo P FAU - Rockstroh, Juergen Kurt AU - Rockstroh JK FAU - Panorchan, Paul AU - Panorchan P FAU - Miller, Michelle AU - Miller M FAU - Caro, Luzelena AU - Caro L FAU - Barnard, Richard AU - Barnard R FAU - Hwang, Peggy May AU - Hwang PM FAU - Gress, Jacqueline AU - Gress J FAU - Quirk, Erin AU - Quirk E FAU - Mobashery, Niloufar AU - Mobashery N LA - eng SI - ClinicalTrials.gov/NCT00704184 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20130607 PL - Netherlands TA - Antiviral Res JT - Antiviral research JID - 8109699 RN - 0 (Antiviral Agents) RN - 0 (Carrier Proteins) RN - 0 (Cyclopropanes) RN - 0 (Indoles) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Isoindoles) RN - 0 (Lactams, Macrocyclic) RN - 0 (NS3 protein, hepatitis C virus) RN - 0 (NS4A cofactor peptide, Hepatitis C virus) RN - 0 (Protease Inhibitors) RN - 0 (Sulfonamides) RN - 0 (Viral Nonstructural Proteins) RN - 9DLQ4CIU6V (Proline) RN - CV3X74AO1H (vaniprevir) RN - GMW67QNF9C (Leucine) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Antiviral Agents/adverse effects/*pharmacokinetics MH - Carrier Proteins/*antagonists & inhibitors/genetics/metabolism MH - Cyclopropanes MH - Drug Resistance, Viral MH - Female MH - Genotype MH - Hepacivirus/*drug effects/enzymology/genetics/isolation & purification MH - Hepatitis C/*drug therapy/virology MH - Humans MH - Indoles/adverse effects/*pharmacokinetics MH - Intracellular Signaling Peptides and Proteins MH - Isoindoles MH - Lactams, Macrocyclic MH - Leucine/analogs & derivatives MH - Male MH - Middle Aged MH - Proline/analogs & derivatives MH - Protease Inhibitors/adverse effects/pharmacokinetics MH - Sulfonamides MH - Viral Nonstructural Proteins/*antagonists & inhibitors/genetics/metabolism MH - Young Adult OTO - NOTNLM OT - AE OT - AUC OT - BMI OT - BUN OT - C(max) OT - C(trough) OT - CI OT - CRU OT - DAA OT - Dose-ranging OT - EC(50) OT - ECG OT - Efficacy OT - GMR OT - GT OT - HCV OT - IC(50) OT - IRF-3 OT - LLoQ OT - MRL OT - Merck Research Laboratories OT - Monotherapy OT - NS3/4A OT - PCR OT - PD OT - PEG-IFN OT - PI OT - PK OT - Pharmacokinetics OT - RAVs OT - RBV OT - SAE OT - SEAP OT - SVR OT - Safety OT - T(max) OT - ULN OT - adverse event OT - area under the concentration-time curve OT - bid OT - blood urea nitrogen OT - body mass index OT - clinical research unit OT - confidence interval OT - direct-acting antiviral OT - electrocardiogram OT - genotype OT - geometric mean ratio OT - half-maximal effective concentration OT - half-maximal inhibitory concentration OT - hepatitis C virus OT - interferon regulatory factor 3 OT - lower limit of quantitation OT - maximum concentration OT - maximum time to reach C(max) OT - nonstructural protein 3/4A OT - once daily OT - pegylated interferon OT - pharmacodynamic(s) OT - pharmacokinetic(s) OT - polymerase chain reaction OT - protease inhibitor OT - qd OT - resistance-associated amino acid variants OT - ribavirin OT - secreted alkaline phosphatase OT - serious adverse event OT - sustained viral response OT - t(1/2) OT - terminal half-life OT - trough concentration OT - twice daily OT - upper limit of normal EDAT- 2013/06/12 06:00 MHDA- 2014/05/03 06:00 CRDT- 2013/06/11 06:00 PHST- 2013/02/04 00:00 [received] PHST- 2013/05/28 00:00 [revised] PHST- 2013/05/30 00:00 [accepted] PHST- 2013/06/11 06:00 [entrez] PHST- 2013/06/12 06:00 [pubmed] PHST- 2014/05/03 06:00 [medline] AID - S0166-3542(13)00155-1 [pii] AID - 10.1016/j.antiviral.2013.05.015 [doi] PST - ppublish SO - Antiviral Res. 2013 Sep;99(3):214-20. doi: 10.1016/j.antiviral.2013.05.015. Epub 2013 Jun 7.