       Document 0826
 DOCN  M9460826
 TI    Clinical pharmacokinetics of zidovudine: inter and intraindividual
       variability and relationship to long term efficacy and toxicity.
 DT    9404
 AU    Mentre F; Escolano S; Diquet B; Golmard JL; Mallet A; INSERM U194,
       Department of Biostatistics and Medical Informatics,; Paris, France.
 SO    Eur J Clin Pharmacol. 1993;45(5):397-407. Unique Identifier : AIDSLINE
       MED/94155926
 AB    The variability of the pharmacokinetics of zidovudine after its oral
       administration to 36 AIDS patients has been investigated by measuring
       the plasma and urine levels of zidovudine and its metabolite on Days 1
       and 35 of continuous treatment. A two-phase absorption model was first
       defined from well-documented data in 12 subjects. The population
       characteristics of the kinetic parameters for both days were estimated
       by a nonparametric method. On Day 1, the mean (coefficient of variation)
       volume of distribution of zidovudine was 94.41 (90%), its mean half-life
       was 0.81 h (107%) and its mean oral clearance was 117 l.h-1 (57%) and on
       Day 35, these values were, respectively, 1121 (139%), 0.75 h (181%) and
       295 l.h-1 (196%). The results confirm the large interindividual and
       intraindividual variation in zidovudine kinetics. The four covariates
       included in the population analysis (body weight, serum haemoglobin,
       creatinine and bilirubin) did not show clear relationship to the kinetic
       parameters. Thirty-four subjects were follow-up clinically for 99 days
       to 367 days after initiation of zidovudine therapy. The relationship
       between individual kinetic parameters (determined by Bayesian
       estimation), mean concentration profiles and outcome was studied through
       survival analysis. Long-term efficacy was defined as the prevention of
       opportunistic infections, which occurred in 13 patients. No clinical or
       kinetic variables, nor the individual zidovudine concentration profiles
       were found to predict the occurrence of an opportunistic infection.
       Toxicity was defined as a 20%-decrease in serum haemoglobin, which
       occurred in 13 patients. A significant relationship between mean daily
       concentration and toxicity was found, with an hazard of occurrence of
       toxicity 4.3-times larger when the mean steady stade concentration was
       0.8 mg.l-1 than 0.6. The results indicate that zidovudine dosage should
       be individualised.
 DE    Acquired Immunodeficiency Syndrome/DRUG THERAPY/*METABOLISM
       Administration, Oral  Adult  Aged  AIDS-Related Complex/DRUG
       THERAPY/*METABOLISM  Bayes Theorem  Human  Middle Age  Reproducibility
       of Results  Support, Non-U.S. Gov't  Survival Analysis
       Zidovudine/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/  *PHARMACOKINETICS
       CLINICAL TRIAL  JOURNAL ARTICLE  MULTICENTER STUDY  RANDOMIZED
       CONTROLLED TRIAL

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

