title: Multiplex liquid chromatography-tandem mass spectrometry assay for simultaneous therapeutic drug monitoring of ribavirin, boceprevir, and telaprevir.
abstract: New directly acting antivirals (DAAs) that inhibit hepatitis C virus (HCV) replication are increasingly used for the treatment of chronic hepatitis C. A marked pharmacokinetic variability and a high potential for drug-drug interactions between DAAs and numerous drug classes have been identified. In addition, ribavirin (RBV), commonly associated with hemolytic anemia, often requires dose adjustment, advocating for therapeutic drug monitoring (TDM) in patients under combined antiviral therapy. However, an assay for the simultaneous analysis of RBV and DAAs constitutes an analytical challenge because of the large differences in polarity among these drugs, ranging from hydrophilic (RBV) to highly lipophilic (telaprevir [TVR]). Moreover, TVR is characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography and must be separated from VRT-127394, its inactive C-21 epimer metabolite. We have developed a convenient assay employing simple plasma protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of levels of RBV, boceprevir, and TVR, as well as its metabolite VRT-127394, in plasma. This new, simple, rapid, and robust HPLC-MS/MS assay offers an efficient method of real-time TDM aimed at maximizing efficacy while minimizing the toxicity of antiviral therapy.
authors: Innovation & Development Laboratory, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors: Manel
authors: M
authors: Aouri
authors: Darius
authors: D
authors: Moradpour
authors: Matthias
authors: M
authors: Cavassini
authors: Thomas
authors: T
authors: Mercier
authors: Thierry
authors: T
authors: Buclin
authors: Chantal
authors: C
authors: Csajka
authors: Amalio
authors: A
authors: Telenti
authors: Andri
authors: A
authors: Rauch
authors: Laurent A
authors: LA
authors: Decosterd
mesh_terms: D000998:Antiviral Agents / Q000097:blood*; D002853:Chromatography, Liquid; D016903:Drug Monitoring / Q000379:methods*; D016174:Hepacivirus / Q000187:drug effects; D006505:Hepatitis / Q000188:drug therapy / Q000517:prevention & control / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000517:prevention & control / Q000821:virology; D009842:Oligopeptides / Q000097:blood* / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D012254:Ribavirin / Q000097:blood* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D012254:Ribavirin; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline
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