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Antimicrob. Agents Chemother. doi:10.1128/AAC.00907-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

THE MULTIPLE-DOSE PHARMACOKINETIC BEHAVIOUR OF ELVUCITABINE, A NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR, WHEN ADMINISTERED OVER 21 DAYS WITH LOPINAVIR/RITONAVIR IN HIV-1 SUBJECTS

Philippe Colucci, John C Pottage, Heather Robison, Jacques Turgeon, Dirk Schrmann, IM Hoepelman, and Murray P. Ducharme^*

Faculté de Pharmacie, University of Montreal, Montreal, Canada; Achillion Pharmaceuticals, Inc., New Haven, CT, USA; Charité-Universitätsmedizin Berlin, Berlin, Germany; University Medical Center, Utrecht, Netherlands; Cetero Research, Cary, NC,USA

^* To whom correspondence should be addressed. Email: murray.ducharme{at}cetero.com.

	Abstract

Purpose: To describe the plasma pharmacokinetics (PK) of elvucitabine at different doses when administered daily or every other day for twenty-one days with Kaletra® in HIV infected subjects.

Methods: Three different dosing regimens of elvucitabine were administered with Kaletra® to 24 subjects with moderate levels of the HIV virus. Plasma samples were collected over 35 days. Elvucitabine concentrations were analyzed using a validated LC-MS/MS assay. The PK of elvucitabine was determined using both noncompartmental and compartmental analyses. Models were developed and tested using ADAPT-II® while a population analysis was performed using IT2S®.

Results: The pharmacokinetic behaviour of elvucitabine was best described by a 2-compartment linear model using two absorption rates and an increase of the bioavailability after Day 1. The augmentation in the bioavailability after Day 1 was variable with some subjects demonstrating a major increase while others had little or none. Elvucitabine has a long half-life of approximately 100 hours.

Conclusions: The increase in elvucitabine bioavailability may be due to ritonavir inhibiting an efflux gut transporter with activity present in varying levels between subjects. The proposed PK model may be utilized and improved further by linking the PK behaviour of elvucitabine to varying markers of efficacy.