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Antimicrobial Agents and Chemotherapy, September 1998, p. 2380-2384, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Safety, Pharmacokinetics, and Antiretroviral Activity of Intravenous 9-[2-(R)-(Phosphonomethoxy)propyl]adenine, a Novel Anti-Human Immunodeficiency Virus (HIV) Therapy, in HIV-Infected Adults

Steven G. Deeks,1,* Patricia Barditch-Crovo,2 Paul S. Lietman,2 Frances Hwang,3 Kenneth C. Cundy,3 James F. Rooney,3 Nicholas S. Hellmann,3,dagger Sharon Safrin,3 and James O. Kahn1

University of California, San Francisco, and San Francisco General Hospital, San Francisco, California1; Johns Hopkins University School of Medicine, Baltimore, Maryland2; and Gilead Sciences, Inc., Foster City, California3

Received 12 November 1997/Returned for modification 14 February 1998/Accepted 18 June 1998

9-[2-(R)-(Phosphonomethoxy)propyl]adenine (PMPA) is a nucleotide analogue with potent antiretroviral activity in vitro and in simian models. A randomized, double-blind, placebo-controlled, dose-escalation clinical trial of intravenous PMPA monotherapy was conducted in 20 human immunodeficiency virus (HIV)-infected adults with CD4 cell counts of >= 200 cells/mm3 and plasma HIV RNA levels of >= 10,000 copies/ml. Two dose levels were evaluated (1 and 3 mg/kg of body weight/day). Ten subjects were enrolled at each dose level (eight randomized to receive PMPA and two randomized to receive placebo). On day 1, a single dose of PMPA or placebo was administered by intravenous infusion. Beginning on study day 8, PMPA or placebo was administered once daily for an additional 7 consecutive days. All subjects tolerated dosing without significant adverse events. Mean peak serum PMPA concentrations were 2.7 ± 0.9 and 9.1 ± 2.1 µg/ml in the 1- and 3-mg/kg cohorts, respectively. Serum concentrations declined in a biexponential fashion, with a terminal half-life of 4 to 8 h. At 3 mg/kg/day, a single infusion of PMPA resulted in a 0.4 log10 median decline in plasma HIV RNA by study day 8. Following 7 consecutive days of study drug administration thereafter, the median changes in plasma HIV RNA from baseline were -1.1, -0.6, and 0.1 log10 in the 3-mg/kg/day, 1-mg/kg/day, and placebo dose groups, respectively. Following the final dose in the 3-mg/kg/day cohort, the reduction in HIV RNA was sustained for 7 days before returning toward baseline. Further studies evaluating an oral prodrug of PMPA are under way.

* Corresponding author. Mailing address: 995 Potrero Ave., San Francisco General Hospital, San Francisco, CA 94110. Phone: (415) 476-4082, ext. 404. Fax: (415) 476-6953. E-mail: sdeeks{at}sfaids.ucsf.edu.

dagger Present address: ViroLogics, Inc., South San Francisco, CA.

Antimicrobial Agents and Chemotherapy, September 1998, p. 2380-2384, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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