PHARMACOKINETIC EVALUATION OF THE COMBINATION OF ZIDOVUDINE AND DIDANOSINE IN CHILDREN WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION

As part of a phase I/II trial in children infected with human immunode ficiency virus, we studied the pharmacokinetics of zidovudine and dida nosine administered as single agents and in combination. Zidovudine (6 0 to 180 mg/m(2) per dose) was given orally every 6 hours, and didanos ine (60 to 180 mg/m(2) per dose) every 12 hours. Pharmacokinetic sampl es were obtained from 54 patients and the area under the plasma concen tration-time curve (AUC) was estimated by means of a previously define d limited sampling strategy. Follow-up blood samples were obtained aft er 4 and 12 weeks of treatment. The mean AUC for zidovudine ranged fro m 4.8 mu mol . hr per liter at 60 mg/m(2) to 11.0 mu mol . hr per lite r at the 180 mg/m(2) level, and increased in proportion to the dose. T he mean AUC for didanosine ranged from 2.8 mu mol . hr per liter (60 m g/m(2)) to 8.0 mu mol hr per liter (180 mg/m(2)), with a wide interpat ient variability. The AUCs of zidovudine and didanosine remained uncha nged when the agents were administered in combination. There was no si gnificant change in the AUCs of either drug after 4 and 12 weeks in co mparison with those on day 3 of therapy. However, there was greater in terpatient and intrapatient variability with didanosine than with zido vudine. These observations have implications far the future utility of therapeutic drug monitoring with these agents.