CLINICAL PHARMACOKINETICS OF ZIDOVUDINE - INTER AND INTRAINDIVIDUAL VARIABILITY AND RELATIONSHIP TO LONG-TERM EFFICACY AND TOXICITY

Citation
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
Citations number
48
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
00316970
Volume
45
Issue
5
Year of publication
1993
Pages
397 - 407
Database
ISI
SICI code
0031-6970(1993)45:5<397:CPOZ-I>2.0.ZU;2-7
Abstract
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.