F. Mentre et al., CLINICAL PHARMACOKINETICS OF ZIDOVUDINE - INTER AND INTRAINDIVIDUAL VARIABILITY AND RELATIONSHIP TO LONG-TERM EFFICACY AND TOXICITY, European Journal of Clinical Pharmacology, 45(5), 1993, pp. 397-407
The variability of the pharmacokinetics of zidovudine after its oral a
dministration to 36 AIDS patients has been investigated by measuring t
he 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 char
acteristics 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-li
fe 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 1.h-1 (196%). The results confirm the large interindivid
ual and intraindividual variation in zidovudine kinetics. The four cov
ariates included in the population analysis (body weight, serum haemog
lobin, creatinine and bilirubin) did not show clear relationship to th
e kinetic parameters. Thirty-four subjects were follow-up clinically f
or 99 days to 367 days after initiation of zidovudine therapy. The rel
ationship between individual kinetic parameters (determined by Bayesia
n estimation), mean concentration profiles and outcome was studied thr
ough survival analysis. Long-term efficacy was defined as the preventi
on of opportunistic infections, which occurred in 13 patients. No clin
ical or kinetic variables, nor the individual zidovudine concentration
profiles were found to predict the occurrence of an opportunistic inf
ection. Toxicity was defined as a 20%-decrease in serum haemoglobin, w
hich occurred in 13 patients. A significant relationship between mean
daily concentration and toxicity was found, with an hazard of occurren
ce of toxicity 4.3-times larger when the mean steady stade concentrati
on was 0.8 mg . l-1 than 0.6. The results indicate that zidovudine dos
age should be individualised.