TY - JOUR
T1 - 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
AU - Deeks, Steven G.
AU - Barditch-Crovo, Patricia
AU - Lietman, Paul S.
AU - Hwang, Frances
AU - Cundy, Kenneth C.
AU - Rooney, James F.
AU - Hellmann, Nicholas S.
AU - Safrin, Sharon
AU - Kahn, James O.
PY - 1998/9
Y1 - 1998/9
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0031710248&partnerID=8YFLogxK
U2 - 10.1128/aac.42.9.2380
DO - 10.1128/aac.42.9.2380
M3 - Article
C2 - 9736567
AN - SCOPUS:0031710248
SN - 0066-4804
VL - 42
SP - 2380
EP - 2384
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 9
ER -