Phase II placebo-controlled trial of fozivudine tidoxil for HIV infection:Pharmacokinetics, tolerability, and efficacy

Fozivudine tidoxil (FZD) is a thioether lipid-zidovudine (ZDV) conjugate wi th anti-HIV activity demonstrated in vitro and in pilot phase I studies. To assess its safety, efficacy and pharmacokinetics, we conducted a multicent er, randomized, double-blind, placebo-controlled trial of FZD monotherapy i n 72 HIV-infected patients who had not previously received antiretroviral t herapy. In each dosage group (200 mg daily, 400 mg daily, 200 mg twice dail y, 800 mg daily, 400 mg twice daily, and 600 mg twice daily), 12 patients w ere randomized to receive in a 10:2 ratio either FZD or a placebo for 4 wee ks. Overall, FZD was well tolerated in all dosage groups; only 1 patient di scontinued the drug, because of a moderate rise in aminotransaminase activi ty. HIV viral load fell in all the patients who were receiving FZD, except in the 200 mg daily group. The largest decrease (-0.67 log(10)) was observe d in the 600 mg twice daily group. The plasma half-life was significantly l onger (-3.8 hours) than that of the parent drug ZDV. Exposure to ZDV, as re flected by the area under the time-concentration curve, was much lower afte r FZD than after ZDV administration. FZD thus appears to be as effective as and potentially better tolerated than ZDV during short-term administration and has the advantage of once daily intake.