The clinical investigations of antiretroviral drugs require that knowledge of the pharmacological parameters of each of these agents in patients with AIDS becomes known. This information may provide explanations for the observed total of organ toxicity induced by the drug and the potential benefits in the fight against the HIV virus. Using this fundamental approach of studying the pharmacology of azidothymidine (AZT) in patients provided significant information on the efficacy and toxicity of this agent. We have investigated the plasma pharmacokinetics of AZT and its glucuronide catabolite (GAZT) in numerous adult and pediatric patients with AIDS. A subset of these studies for a total of 24 doses after oral administration of 200 mg AZT per dose showed that the peak plasma AZT concentrations ranged from 0.954 to 8.13 micro m and averaged 4.18 plus minus 1.97 micro m (n=24 plus/minus S. Dev.) and the through AZT concentrations ranged from 0.015 to 0.81 at 4 hours and averaged 0.31 plus/minus 0.23 micro m (n=22 plus/minus S. Dev). The elimination kinetics of AZT was monoexponetial in nature with an average (t 1/2) of elimination of 40.02 plus/minus 10.3 min. The effect of sulfa drugs (Fancidar) and/or food intake on AZT plasma concentrations was substantial, in that it yielded lower peak plasma concentrations by 2- to 3-fold. However, the (t 1 2), el was longer by approximately 2.5-fold after food and/or sulfa drug administration and the overall AUC of AZT with and without food or sulfa drugs was on average similar in all subjects studied. The Mean Residence Time (MRT) oa AZT increased significantly after food or sulfa drug ingestion from 0.83 plus/minus 0.07 hr-1 in the subjects studied. The data suggest that co-administration of AZT with sulfa drugs and food may have a significant decrease in peak plasma concentration but only a qualitative influence in the AUC. GAZT was accumulated in higher peak plasma levels than AZT in all patients studied and it was eliminated monoexponentially with a (t 1 2), el of 58.2 plus/minus 21 minutes (n=9 plus/minus S. Dev.). In the patients who received two consecutive doses of AZT every 4 hours no apparent accumulation of AZT concentrations in plasma was observed. Similarly the pharmacokinetic studies of Gomcyclonir have been analyzed with or without co-administration of interferon alpha. These analyses required both analytical and pharmacokinetic expertise which the laboratory provided to ACTG. Future studies will attempt to determine the pharmacokinetics and elucidate the antiviral effect of other anti-HIV drugs administered alone or in combination with AZT in AIDS patients.
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