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

Abstract

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 microgram/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.

FIG. 1

Mean concentrations of PMPA in serum. Mean concentrations, with standard deviations of PMPA in serum following daily intravenous infusions of PMPA.

FIG. 2

Median log₁₀ change in plasma HIV-1 RNA levels from that at baseline. Top line (with boxes), placebo; middle line (with circles), 1-mg/kg/day dose; bottom line (with boxes), 3-mg/kg/day dose. Vertical bars represent values from quartile 1 to quartile 3 for each dosing cohort.

FIG. 3

Median AUC on day 1 versus median antiviral response on day 14. Median AUC on day 1 for placebo, 1-mg/kg/day, and 3-mg/kg/day dose groups versus the median decrease in log₁₀ plasma HIV RNA levels from baseline on day 14. Vertical bars represent the standard error.