DOSE PROPORTIONALITY OF STAVUDINE IN HIV-SEROPOSITIVE ASYMPTOMATIC SUBJECTS - APPLICATION TO BIOEQUIVALENCE ASSESSMENT OF VARIOUS CAPSULE FORMULATIONS

The dose proportionality and bioequivalence of the capsule formulation s used in clinical trials and the proposed commercial formulations of stavudine were assessed in an open-label, single-dose, randomized four -way crossover study in 16 asymptomatic HIV-infected males. One capsul e of stavudine (5, 10, 20, or 40 mg) was administered orally to each s ubject in each of the four treatment periods. Serial blood samples wer e collected for 10 h after each dose and the plasma was assayed for in tact stavudine by a validated radioimmunoassay method. The plasma conc entration-time data were subjected to noncompartmental pharmacokinetic analysis. For doses ranging from 5 to 40 mg, mean C-max and AUC(0-inf inity), values were in the range of 110.36-889.34 ng mL(-1) and 246-46 -1945.97 h ng mL(-1) respectively. The mean C-max and AUC(0-infinity)f stavudine increased in a dose-proportional manner. Irrespective of th e dose, mean C-max values were observed at a median t(max) of 0.75 h o r less. Mean tip values were 1.97, 1.77, 1.67 and 1.66 h for the 5, 10 , 20, and 40 mg capsules, respectively. For bioequivalence assessment, C-max and AUC(0-infinity), values were normalized to the 10 mg dose s ince these parameters were dose proportional. The 10 mg capsule formul ation used in phase-3 clinical trials was chosen as the reference. The relative bioavailability estimates and 90% confidence limits for the dose-normalized C-max values with the 10 mg capsule as the reference w ere 86% (76%, 96%), 99% (88%, 110%), and 90% (80%, 100%) for the 5, 20 , and 40 mg capsules, respectively. The differences in the point estim ates of the dose-normalized AUC(0-infinity), values for the 5, 20, and 40 mg capsules relative to the 10 mg phase-3 capsule were 1% or less, and the 90% confidence limits were all within 95-106%. These results indicate that stavudine exhibits linear pharmacokinetics and that the 5, 10, 20, and 40 mg capsules of stavudine are bioequivalent.