A phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection.

To determine the pharmacokinetic properties, tolerance, safety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children. Phase I/II, open and dose-ranging (0.125 to 4 mg/kg/day in two divided doses). Thirty-seven HIV-infected children (median age, 5.5 years; range, 7 months to 15 years) with a median CD4+ lymphocyte count at baseline of 242 cells/microL (range 2 to 2290 cells/microL). Thirty children had symptomatic HIV disease at entry; seven had HIV-related immunosuppression alone. Twenty-nine subjects had a history of prior zidovudine (ZDV) therapy. As compared with adults receiving the same weight-adjusted doses, the children we studied had lower maximum observed stavudine plasma concentrations (CMAX) and area under the plasma concentration versus time curves (AUC), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plasma accumulation of the drug between day 1 and week 12. Week 12 cerebrospinal fluid stavudine concentrations in seven subjects, obtained approximately 2 to 3 hours after oral doses, ranged from 16% to 97% of concomitant plasma concentrations. Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subject with baseline neurologic abnormalities experienced a transient episode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying disease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some subjects. Progression of HIV disease and survival correlated with prior ZDV therapy, HIV disease classification, baseline CD4+ lymphocyte count, and weight growth velocity. Stavudine appears to hold promise for the treatment of HIV infection in children. Its pharmacokinetic properties are consistent and predictable, and it appears to be remarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory evidence of activity was observed.