A PHASE I II EVALUATION OF STAVUDINE (D4T) IN CHILDREN WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION/

Objectives. To determine the pharmaco-kinetic properties, tolerance, s afety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children. Design. Phase I/II, open and dose-rang ing (0.125 to 4 mg/kg/day in two divided doses). Patients. Thirty-seve n 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/mu L (range 2 to 2290 cells/mu L). Thirty children had symptomatic HIV d isease at entry; seven had HIV-related immunosuppression alone. Twenty -nine subjects had a history of prior zidovudine (ZDV) therapy. Result s. As compared with adults receiving the same weight-adjusted doses, t he children we studied had lower maximum observed stavudine plasma con centrations (CMAX) and area under the plasma concentration versus time curves (AUG), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plas ma accumulation of the drug between day 1 and week 12. Week 12 cerebro spinal fluid stavudine concentrations in seven subjects, obtained appr oximately 2 to 3 hours after oral doses, ranged from 16% to 97% of con comitant plasma concentrations. Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subje ct with baseline neurologic abnormalities experienced a transient epis ode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying dis ease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some sub jects. Progression of HIV disease and survival correlated with prior Z DV therapy, HIV disease classification, baseline CD4+ lymphocyte count , and weight growth velocity. Conclusions. Stavudine appears to hold p romise for the treatment of HIV infection in children. Its pharmacokin etic properties are consistent and predictable, and it appears to be r emarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory ev idence of activity was observed.