Document 0138
 DOCN  M9590138
 TI    Dose proportionality of stavudine in HIV seropositive asymptomatic
       subjects: application to bioequivalence assessment of various capsule
       formulations.
 DT    9509
 AU    Kaul S; Mummaneni V; Barbhaiya RH; Bristol-Myers Squibb Pharmaceutical
       Research Institute, Syracuse,; NY 08543-4000, USA.
 SO    Biopharm Drug Dispos. 1995 Mar;16(2):125-36. Unique Identifier :
       AIDSLINE MED/95299037
 AB    The dose proportionality and bioequivalence of the capsule formulations
       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
       capsule of stavudine (5, 10, 20, or 40 mg) was administered orally to
       each subject in each of the four treatment periods. Serial blood samples
       were collected for 10 h after each dose and the plasma was assayed for
       intact stavudine by a validated radioimmunoassay method. The plasma
       concentration-time data were subjected to non-compartmental
       pharmacokinetic analysis. For doses ranging from 5 to 40 mg, mean Cmax
       and AUC0-infinity 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 Cmax and AUC0-infinity
       of stavudine increased in a dose-proportional manner. Irrespective of
       the dose, mean Cmax values were observed at a median tmax of 0.75 h or
       less. Mean t1/2 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,
       Cmax and AUC0-infinity values were normalized to the 10 mg dose since
       these parameters were dose proportional. The 10 mg capsule formulation
       used in phase-3 clinical trials was chosen as the reference. The
       relative bioavailability estimates and 90% confidence limits for the
       dose-normalized Cmax values with the 10 mg capsule as the reference were
       86% (76%, 96%), 99% (88%, 110%), and 90% (80%, 100%) for the 5, 20, and
       40 mg capsules, respectively. The differences in the point estimates of
       the dose-normalized AUC0-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.
 DE    Adult  Capsules  Cross-Over Studies  Half-Life  Human  HIV
       Infections/*DRUG THERAPY/*METABOLISM  Male  Stavudine/*ADMINISTRATION &
       DOSAGE/*PHARMACOKINETICS  Therapeutic Equivalency  CLINICAL TRIAL
       CLINICAL TRIAL, PHASE III  JOURNAL ARTICLE  RANDOMIZED CONTROLLED TRIAL

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).