8th International AIDS Conference Amsterdam, Netherlands — July 19-24, 1992

Int Conf AIDS 1992 Jul 19-24; 8:We47 (abstract no. WeB 1011)
Dunkle L, Anderson R, McLaren C, Cross A, Brown M, Gugliotti R, Adler M, Kaul S; Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, CT.

OBJECTIVES: To determine the pharmacokinetics and preliminary evidence of safety, activity, and efficacy of Stavudine (d4T) in HIV seropositive patients with fewer than 500 CD4+ cells/ul.

METHODS: d4T was administered orally in 2, 3 and 4 daily doses totaling 0.1 to 12.0 mg/kg/day to 264 patients in 6 Phase I and II clinical trials conducted at 10 sites. The duration of treatment ranges from 3 months to 2.3 years. Clinical and laboratory markers of toxicity and efficacy were measured throughout, and data from all studies were combined for analysis.

RESULTS: d4T exhibited oral bioavailability of greater than 85% and low variability of area under the plasma concentration vs time curve (less than 20%) for fixed doses under 80 mg. Improvements in CD4+ counts, declines in p24 antigen, weight gain, and improvement in general well being were seen on therapy. The median duration of improvement in CD4+ counts in patients who had a 50% increase on therapy exceeded one year. At doses of less than 2.0 mg/kg/day, 29% of patients experienced some dose modification and 16% discontinued the study during the first six months of therapy. Adverse events were observed primarily at higher doses, and included peripheral neuropathy and transaminase elevations. The drug was well tolerated by the 139 patients receiving doses of less than 2.0 mg/kg/day.

CONCLUSIONS: D4T appears to be an active anti-retroviral agent with prolonged effect in some patients and a good safety profile. Phase III studies comparing d4T with AZT and further evaluating different doses of d4T are planned.

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