title: Intracellular and Plasma Trough Concentration and Pharmacogenetics of Telaprevir.
abstract: OBJECTIVE
  Triple therapy for HCV-1 infection consists in boceprevir or telaprevir, ribavirin and PEG-interferon. Telaprevir is a P-glycoprotein substrate and it is metabolized by CYP3A4/5. No data have been published on intracellular penetration of telaprevir. We determined peripheral blood mononuclear cells (PBMCs) and trough plasma S and R telaprevir isomers concentrations; moreover, we evaluated the influence of some single nucleotide polymorphisms (SNPs) on these pharmacokinetic data after 1 month of triple therapy in humans.
  
  
  METHODS
  Plasma and intracellular telaprevir concentrations were determined at the end of dosing interval (Ctrough) using ULPC-MS/MS validated methods; allelic discrimination was performed through real-time PCR.
  
  
  RESULTS
  Median telaprevir Ctrough plasma concentrations were 2579 ng/mL and 2233 ng/mL for the pharmacologically more active S, and R, enantiomers, respectively, with median S/R plasma ratio of 1.11. In PBMC, the medians were 6863 ng/mL and 1096 ng/mL for S and R, respectively, with median S/R being 5.73. The PBMC:plasma ratio for S was 2.59 for R. Plasma ribavirin concentrations were directly correlated with plasma S-telaprevir concentrations. In linear regression analysis, only CYP24A1_rs2585428 SNP (p=0.003) and body mass index (p=0.038) were able to predict S-telaprevir PBMC concentrations.
  
  
  CONCLUSIONS
  Our preliminary data could increase the understanding of mechanisms underlying telaprevir intracellular and plasma exposure, suggesting the implementation of pharmacogenetics in these drug kinetic studies.
authors.affiliation: Department of Medical Sciences, Infectious Diseases Unit, Amedeo di Savoia Hospital, University of Turin, Turin, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cusato
authors.forename: Sarah
authors.initials: S
authors.lastname: Allegra
authors.forename: Amedeo
authors.initials: A
authors.lastname: De Nicolò
authors.forename: Lucio
authors.initials: L
authors.lastname: Boglione
authors.forename: Giovanna
authors.initials: G
authors.lastname: Fatiguso
authors.forename: Adnan
authors.initials: A
authors.lastname: Mohamed Abdi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cariti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012044:Regression Analysis; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D012254:Ribavirin; C486464:telaprevir