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Antimicrobial Agents and Chemotherapy, November 2002, p. 3428-3436, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3428-3436.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vivo Toxicity, Pharmacokinetics, and Anti-Human Immunodeficiency Virus Activity of Stavudine-5'-(p-Bromophenyl Methoxyalaninyl Phosphate) (Stampidine) in Mice

Fatih M. Uckun,* Sanjive Qazi, Sharon Pendergrass, Elizabeth Lisowski, Barbara Waurzyniak, Chun-Lin Chen, and T. K. Venkatachalam

Drug Discovery Program, Departments of Virology, Immunology, Pathology, Pharmaceutical Sciences, and Chemistry, Parker Hughes Institute, St. Paul, and Parker Hughes Center for Clinical Immunology, Roseville, Minnesota

Received 28 February 2002/ Returned for modification / Accepted 15 July 2002

We have evaluated the clinical potential of stavudine-5'-(p-bromophenyl methoxyalaninyl phosphate(stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, as a new anti-human immunodeficiency virus (anti-HIV) agent, by examining its acute, subacute, and chronic toxicity profile in mice as well as by testing its antiviral activity in a surrogate human peripheral blood lymphocyte (Hu-PBL)-SCID mouse model of human AIDS. STAMP was very well tolerated in BALB/c and CD-1 mice, without any detectable acute or subacute toxicity at single intraperitoneal or oral bolus doses as high as 500 mg/kg of body weight. Notably, daily administration of STAMP intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg. Micromolar concentrations of the active STAMP metabolite in plasma were rapidly achieved and maintained for more than 4 h after parenteral as well as oral administration of a nontoxic 100-mg/kg bolus dose of STAMP. In accordance with its favorable pharmacokinetic profile and in vitro potency, STAMP exhibited dose-dependent and potent in vivo anti-HIV activity in Hu-PBL-SCID mice against a genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant clinical HIV type 1 (HIV-1) isolate (BR/92/019; D67N, L214F, T215D, K219Q) at nontoxic dose levels. The remarkable in vivo safety and potency of STAMP warrants the further development of this promising new antiretroviral agent for possible clinical use in patients harboring NRTI-resistant HIV-1.

* Corresponding author. Mailing address: Parker Hughes Institute, 2699 Patton Rd., St. Paul, MN 55113. Phone: (651) 796-5450. Fax: (651) 796-5493. E-mail: fatih_uckun{at}ih.org.

Antimicrobial Agents and Chemotherapy, November 2002, p. 3428-3436, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3428-3436.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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