PHARMACOKINETIC VARIABILITY OF ZIDOVUDINE IN HIV-INFECTED INDIVIDUALS- SUBGROUP ANALYSIS AND DRUG-INTERACTIONS

Objective: To investigate determinants of inter- and intraindividual v ariability of zidovudine (ZDV) pharmacokinetics in HIV-infected patien ts. Design: A prospective study in a general 525-bed hospital with spe cial funding for treatment and research of HIV-infected patients. Meth ods: Serial blood samples were collected from 68 HIV-infected individu als providing a total of 95 pharmacokinetic curves. ZDV was measured w ith high-performance liquid chromatography and radioimmunoassay. Pharm acokinetic parameters were calculated by non-compartmental analysis. P atient characteristics were investigated by multivariate analysis for an influence on ZDV pharmacokinetics. Results: Apparent ZDV clearance was significantly lower in patients with a lower body weight, in women , and in patients with a more advanced stage of HIV disease. Co-admini stration of methadone with ZDV resulted in higher plasma concentration s of ZDV, while rifampin and ganciclovir increased apparent ZDV cleara nce. Age, the duration of ZDV use, CD4+ cell count, creatinine clearan ce, elevated serum liver enzyme levels, and the use of 11 other co-adm inistered medications were not independently related to apparent ZDV c learance. Conclusions: The pharmacokinetic profile of ZDV in several s ubpopulations has been evaluated, as well as the observation of possib le drug-drug interactions between ZDV and 14 different drugs or groups of drugs. These data suggest that patient-individualized antiretrovir al therapy may be appropriate once pharmacokinetic-pharmacodynamic rel ationships have been established.