Single Dose Escalation Study Research Articles

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 IC 50 of 0.08 μM against HIV-1 (strain IIIB) and a mean IC 50 of 0.012 μM against 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 synergistic with saquinavir and additive with either indinavir or ritonavir. Resistance to 141W94 has been reported in vitro passage experiments. The binding of 141W94 to human α 1-acid glycoprotein was relatively weak (Kd = 4 μM) and the off-rate for the drug is very fast (≥ 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 Phase I placebo-controlled, single-dose escalation, pharmacokinetic and safety study. The average concentration of 1 41W94 at 8 and 12 h after single doses of 900 and 1200 mg, respectively, was in excess of 10 times the IC 50. As 141W94 is synergistic with a variety of anti-HIV-1 agents and exhibits a unique cross resistance profile compared to other protease inhibitors, 141W94 is considered a good candidate for combination therapy.