title: Intracellular accumulation of boceprevir according to plasma concentrations and pharmacogenetics.
abstract: Boceprevir (BOC) is a directly-acting antiviral agent for the treatment of hepatitis C virus genotype 1 (HCV-1) infection. It is a mixture of two stereoisomers, the inactive R and the active S isomers. No data have previously been published on BOC intracellular accumulation. In this study, BOC isomer concentrations in peripheral blood mononuclear cells (PBMCs) and plasma were determined. The influence of various single nucleotide polymorphisms (SNPs) on plasma and intracellular drug exposure at Week 4 of triple therapy were also evaluated. Plasma and intracellular BOC concentrations were determined at the end of the dosing interval (C(trough)) using a UPLC-MS/MS validated method. Allelic discrimination was performed through real-time PCR. Median plasma concentrations were 65.97 ng/mL for the S isomer and 36.31 ng/mL for the R isomer; the median S/R plasma concentration ratio was 1.66. The median PBMC concentration was 2285.88 ng/mL for the S isomer; the R isomer was undetectable within PBMCs. The median S isomer PBMC/plasma concentration ratio was 28.59. A significant positive correlation was found between plasma and PBMC S isomer concentrations. ABCB1 1236, SLC28A2 124 and IL28B rs12979860 SNPs were associated with the S isomer PBMC/plasma concentration ratio. In regression models, S isomer plasma levels and FokI polymorphism were able to predict S isomer intracellular exposure, whereas SNPs in AKR1, BCRP1 and SLC28A2 predicted the S isomer PBMC/plasma concentration ratio. No similar data regarding BOC pharmacogenetics and pharmacokinetics have been published previously. This study adds a novel and useful overview of the pharmacological properties of this drug.
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy. Electronic address: jessica.cusato@yahoo.it.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cusato
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Allegra
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: De Nicolò
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Boglione
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Fatiguso
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Adnan Mohamed
authors.initials: AM
authors.lastname: Abdi
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cariti
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000737:chemistry*; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000737:chemistry*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D010597:Pharmacogenetics; D010949:Plasma / Q000737:chemistry*; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D000095022:Interferon Lambda
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000998:Antiviral Agents; D007372:Interferons; D007378:Interleukins; D026901:Membrane Transport Proteins; D011392:Proline; C513055:ABCB1 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C065171:cif nucleoside transporter; 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
keywords: ABCB1; AKR1; BCRP1; FokI; IL28B; SLC28A2