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Multiple-Dose Pharmacokinetics of Apricitabine, a Novel Nucleoside Reverse Transcriptase Inhibitor, in Patients with HIV-1 Infection

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Abstract

Background and objective: This study aimed to investigate the multiple-dose pharmacokinetics of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor, in antiretroviral-naive patients with HIV-1 infection.

Methods: This was an international, randomized, double-blind, placebo-controlled, multicentre, dose-ranging study. Patients received 10 days’ oral placebo or apricitabine 200, 400, 600 or 800 mg twice daily or 800 or 1200 mg once daily. On days 1 and 8, blood and urine samples were collected over 24 hours for pharmacokinetic analysis. Apricitabine triphosphate pharmacokinetics were investigated in peripheral blood mononuclear cells (PBMCs) on day 8.

Results: Overall, 63 patients (mean age 33.9 ± 8.7 years; mean weight 71.6 ± 15.4 kg) were randomized, and 62 patients completed the study. Apricitabine was rapidly absorbed, with peak plasma concentrations attained within approximately 1.5–2.5 hours. Pharmacokinetics were linear over the range 200–800 mg twice daily. Apricitabine was predominantly excreted via the kidneys, with no significant accumulation during repeated administration. Steady-state conditions were attained by day 8. Apricitabine triphosphate exposure in PBMCs was roughly proportional to the dose of apricitabine across the dose range 200–800 mg twice daily, with adequate correlations between plasma exposure to apricitabine (9910 ng/mL per 65 kg for 800-mg twice-daily administration) and PBMC exposure to apricitabine triphosphate (maximum concentration [Cmax] = 5.55 ± 1.94 pmol/million cells for 800-mg twice-daily administration). Apricitabine was well tolerated.

Conclusion: Apricitabine shows essentially linear pharmacokinetics during repeated administration in patients with HIV-1 infection.

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Acknowledgements

Funding for this study was provided by Shire Pharmaceutical Development Inc., Rockville, MD, USA.

L. Shiveley is an employee of Shire Pharmaceutical Development, Inc. T. Holdich was an employee of Shire Pharmaceuticals, UK. P. Cahn and J. Sawyer have acted as consultants to Avexa Ltd. The other authors have no conflicts of interest that are directly relevant to the content of this study.

The authors would like to thank Dr S. Cox of Avexa Ltd for her critical review and support with additional pharmacokinetic analyses. Thanks also go to Dr M. Quinn of Prism Ideas Ltd for his assistance in the drafting of this manuscript.

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Authors and Affiliations

  1. Fundación Huésped, Buenos Aires, Argentina

    Pedro Cahn

  2. Hospital Fernandez, Buenos Aires, Argentina

    Maria Rolon

  3. Helios Salud, Buenos Aires, Argentina

    Isabel Cassetti

  4. Shire Pharmaceutical Development Inc., Wayne, Pennsylvania, USA

    LeeAnn Shiveley

  5. Formerly of Shire Pharmaceuticals, Basingstoke, Hampshire, UK

    Tom Holdich

  6. Prism Ideas, Regent House, Princes Court, Beam Heath Way, Nantwich, CW5 6PQ, Cheshire, UK

    James Sawyer

Authors
  1. Pedro Cahn
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  2. Maria Rolon
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  3. Isabel Cassetti
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  4. LeeAnn Shiveley
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  5. Tom Holdich
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  6. James Sawyer
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Correspondence to James Sawyer.

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Cahn, P., Rolon, M., Cassetti, I. et al. Multiple-Dose Pharmacokinetics of Apricitabine, a Novel Nucleoside Reverse Transcriptase Inhibitor, in Patients with HIV-1 Infection. Clin. Drug Investig. 28, 129–138 (2008). https://doi.org/10.2165/00044011-200828020-00007

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  • DOI: https://doi.org/10.2165/00044011-200828020-00007

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