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

9-[2-(R)-(Phosphonomethoxy)propyl]adenine (PMPA) is a nucleotide analo gue with potent antiretroviral activity in vitro and in simian models. A randomized, double-blind, placebo-controlled, dose escalation clini cal trial of intravenous PMPA monotherapy was conducted in 20 human im munodeficiency virus (HIV)-infected adults with CD4 cell counts of gre ater than or equal to 200 cells/mm(3) and plasma HIV RNA levels of gre ater than or equal to 10,000 copies/ml. Two dose levels were evaluated (1 and 3 mg/kg of body weight/day), Ten subjects were enrolled at eac h dose level (eight randomized to receive PMPA and two randomized to r eceive placebo). On day 1, a single dose of PMPA or placebo was admini stered by intravenous infusion. Beginning on study day 8, PMPA or plac ebo 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 mu g/ ml in the 1- and 3-mg/kg cohorts, respectively. Serum concentrations d eclined 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 log(1 0) median decline in plasma HIV RNA by study day 8, Following 7 consec utive days of study drug administration thereafter, the median changes in plasma HIV RNA from baseline were -1.1, -0,6, and 0.1 log(10) in t he 3-mg/kg/day, 1-mg/kg/day, and placebo dose groups, respectively, Fo llowing the final dose in the 3-mg/kg/day cohort, the reduction in HN RNA was sustained for 7 days before returning toward baseline. Further studies evaluating an oral prodrug of PMPA are under way.