Mh. Stclair et al., IN-VITRO ANTIVIRAL ACTIVITY OF 141W94 (VX-478) IN COMBINATION WITH OTHER ANTIRETROVIRAL AGENTS, Antiviral research, 29(1), 1996, pp. 53-56
141W94 (VX-478) is a novel HIV-1 protease inhibitor with an IC50 of 0.
08 mu M against HIV-1 (strain IIIB) and a mean IC50 of 0.012 mu M agai
nst six HIV clinical isolates. 141W94 was synergistic on the basis of
isobologram analysis with each of the following reverse transcriptase
inhibitors: AZT, 935U83, 524W91, 1592U89 and ddl. 141W94 was also syne
rgistic with saquinavir and additive with either indinavir or ritonavi
r. Resistance to 141W94 has been reported in vitro passage experiments
. The binding of 141W94 to human alpha(1)-acid glycoprotein was relati
vely weak (Kd = 4 mu M) and the off-rate for the drug is very fast (gr
eater than or equal to 100 s(-1)). Only a 2-fold reduction of in vitro
antiviral activity was observed in the presence of 45% human plasma.
No serious drug associated adverse experiences were reported in a Phas
e I placebo-controlled, single-dose escalation, pharmacokinetic and sa
fety study. The average concentration of 1 41W94 at 8 and 12 h after s
ingle doses of 900 and 1200 mg, respectively, was in excess of 10 time
s the IC50. As 141W94 is synergistic with a variety of anti-HIV-1 agen
ts and exhibits a unique cross resistance profile compared to other pr
otease inhibitors, 141W94 is considered a good candidate for combinati
on therapy.