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Antimicrobial Agents and Chemotherapy, August 2007, p. 2943-2947, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.01013-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effect of Lamivudine on the Plasma and Intracellular Pharmacokinetics of Apricitabine, a Novel Nucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers{triangledown}

T. Holdich,1* L. A. Shiveley,2 and J. Sawyer3,4

Shire Pharmaceuticals, Ltd., Basingstoke, United Kingdom,1 Shire Pharmaceutical Development, Inc., Wayne, Pennsylvania,2 Prism Ideas, Nantwich, United Kingdom,3 Avexa, Melbourne, Victoria, Australia4

Received 14 August 2006/ Returned for modification 17 October 2006/ Accepted 8 January 2007

Apricitabine is a novel deoxycytidine analog reverse transcriptase inhibitor. In vitro apricitabine competes with other deoxycytidine analogues for intracellular phosphorylation mediated by deoxycytidine kinase. The topic of this study, the effect of concomitant administration of apricitabine and lamivudine on the plasma and intracellular pharmacokinetics of the two compounds, was investigated in healthy volunteers. Participants (n = 21; age, 18 to 30 years) received apricitabine at 600 mg twice daily, lamivudine at 300 mg once daily, and the two treatments in combination for 4 days each in random order. Plasma, urine, and intracellular pharmacokinetics were assessed on day 4 of each treatment period. Apricitabine was rapidly absorbed after oral administration, with peak concentrations being attained after a mean of 1.76 h. Coadministration with lamivudine had no significant effect on the plasma and urine pharmacokinetics of apricitabine. However, the formation of apricitabine triphosphate in peripheral blood mononuclear cells was markedly reduced after the coadministration of apricitabine and lamivudine than after the administration of apricitabine alone: the area under the concentration-time curve from 0 to 12 h for apricitabine triphosphate during combination treatment was ca. 15% of that seen after the administration of apricitabine alone. In contrast, apricitabine had no effect on the plasma pharmacokinetics of lamivudine or on the formation of lamivudine triphosphate in peripheral blood mononuclear cells. These results are consistent with in vitro findings that lamivudine inhibits the intracellular phosphorylation of apricitabine. In conjunction with similar in vitro observations for emtricitabine and apricitabine, these results suggest that apricitabine should not be coadministered with other deoxycytidine analogues for the treatment of human immunodeficiency virus infection.

* Corresponding author. Mailing address: Prism Ideas, Regent House, Princes Court, Beam Heath Way, Nantwich CW5 6PQ, United Kingdom. Phone: 44 (0) 1270 621724. Fax: 44 (0) 1270 621725. E-mail: james.sawyer{at}prismideas.com

{triangledown} Published ahead of print on 22 January 2007.

Antimicrobial Agents and Chemotherapy, August 2007, p. 2943-2947, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.01013-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Gaffney, M. M, Belliveau, P. P, Spooner, L. M (2009). Apricitabine: A Nucleoside Reverse Transcriptase Inhibitor for HIV Infection. The Annals of Pharmacotherapy 43: 1676-1683 [Abstract] [Full Text]  
  • Bethell, R., De Muys, J., Lippens, J., Richard, A., Hamelin, B., Ren, C., Collins, P. (2007). In Vitro Interactions between Apricitabine and Other Deoxycytidine Analogues. Antimicrob. Agents Chemother. 51: 2948-2953 [Abstract] [Full Text]  


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