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Antimicrobial Agents and Chemotherapy, April 2009, p. 1532-1538, Vol. 53, No. 4
0066-4804/09/$08.00+0 doi:10.1128/AAC.01000-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Steady-State Pharmacokinetics of Abacavir in Plasma and Intracellular Carbovir Triphosphate following Administration of Abacavir at 600 Milligrams Once Daily and 300 Milligrams Twice Daily in Human Immunodeficiency Virus-Infected Subjects
Graeme Moyle,1
Marta Boffito,1
Carl Fletcher,1
Chris Higgs,1
Phillip E. Hay,2
Ivy H. Song,3*
Yu Lou,3
Geoffrey J. Yuen,3,
Sherene S. Min,3 and
Elena M. Guerini4
St. Stephen's Centre, Chelsea and Westminster Hospital, London, United Kingdom,1 Genito-Urinary Medicine, St. Georges Hospital, London, United Kingdom,2 GlaxoSmithKline, Research Triangle Park, North Carolina,3 GlaxoSmithKline, Stevenage, United Kingdom4
Received 25 July 2008/ Returned for modification 20 November 2008/ Accepted 20 January 2009
Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days –1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC0-24) and comparable CBV-TP concentrations at the end of the dosing interval (C
). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (Cmax) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC0-24 and 99% higher CBV-TP Cmax than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC0-24 and 81% higher weight-adjusted CBV-TP AUC0-24 than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.
* Corresponding author. Mailing address: GlaxoSmithKline 17-2229.2B, 5 Moore Drive, Research Triangle Park, NC 27709. Phone: (919) 483-7197. Fax: (919) 315-0440. E-mail: ivy.h.song{at}gsk.com
Published ahead of print on 2 February 2009.
Present address: Gilead Science, Durham, NC.
Antimicrobial Agents and Chemotherapy, April 2009, p. 1532-1538, Vol. 53, No. 4
0066-4804/09/$08.00+0 doi:10.1128/AAC.01000-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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