IN-VITRO ANTIVIRAL ACTIVITY OF 141W94 (VX-478) IN COMBINATION WITH OTHER ANTIRETROVIRAL AGENTS

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.