International Journal of Antimicrobial Agents 45 (2015) 657–661 Contents lists available at ScienceDirect International Journal of Antimicrobial Agents j o ur nal ho me pag e: http://www.elsevier.com/locate/ijantimicag Short Communication Intracellular accumulation of boceprevir according to plasma concentrations and pharmacogenetics Jessica Cusato ∗,1 , Sarah Allegra 1 , Amedeo De Nicolò, Lucio Boglione, Giovanna Fatiguso, Adnan Mohamed Abdi, Giuseppe Cariti, Giovanni Di Perri, Antonio D’Avolio Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, 10149 Turin, Italy a r t i c l e i n f o Article history: Received 2 December 2014 Accepted 31 January 2015 Keywords: ABCB1 SLC28A2 IL28B AKR1 BCRP1 FokI a b s t r a c t 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. © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. 1. Introduction Approval of the ﬁrst-generation protease inhibitors bocepre- vir (BOC) and telaprevir (TVR) in 2011 changed the standard of care for hepatitis C virus genotype 1 (HCV-1) infection from dual to triple therapy. BOC or TVR plus ribavirin (RBV) and pegylated interferon-alfa (PEG-IFN) is associated with an improvement in the sustained virological response (SVR) rate both for naïve and experienced HCV-1 patients [1]. BOC-based triple therapy consists ∗ Corresponding author. Present address: Laboratory of Clinical Pharmacology and Pharmacogenetics [UNI EN ISO 9001:2008 Certiﬁed Laboratory; Certiﬁcate No. IT-64386; Certiﬁcation for ‘Design, development and application of determination methods for anti-infective drugs. Pharmacogenetic analyses.’], Unit of Infectious Diseases, University of Torino, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy. Tel.: +39 011 439 3841; fax: +39 011 439 3996. E-mail address: jessica.cusato@yahoo.it (J. Cusato). 1 These two authors contributed equally to this work. of a 48-week treatment duration and it is a good choice for those unable to tolerate the adverse effects of TVR [2]. BOC is a peptidomimetic -ketoamide that is able to reversibly bind the serine-139 active site of HCV NS3/4A protease, halting viral replication. This drug is a mixture of two interconvertible diastereoisomers: SCH-534128 (the S isomer) is 41–130-fold more active and has ca. 2-fold higher systemic exposure than SCH- 534129 (the R isomer) [3]. BOC is metabolised by cytochromes P450 3A4/5 and aldo-keto reductase (AKR) 1C2/3; the keto-reduced metabolites do not have antiviral activity and they are the most abundant metabolite present in the bloodstream [4]. BOC is mainly eliminated by the liver (80%) and a small percentage by the kid- ney (10%) [3]. No data have been published on the intracellular accumulation of BOC. In this study, plasma and intracellular BOC concentrations were determined using the easily accessible peripheral blood mono- nuclear cells (PBMCs) as a model for drug penetration. Moreover, the inﬂuence of various single nucleotide polymorphisms (SNPs) in genes involved in BOC and RBV transport and the vitamin D http://dx.doi.org/10.1016/j.ijantimicag.2015.01.019 0924-8579/© 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.