PHARMACOKINETICS OF SAQUINAVIR, ZIDOVUDINE, AND ZALCITABINE IN COMBINATION THERAPY

We investigated the pharmacokinetics of zidovudine, zalcitabine, and s aquinavir in AIDS Clinical Trial Group protocol 229. Patients received either saquinavir, zalcitabine, or a combination of both, together wi th zidovudine three times a day, Approximately 100 patients were enrol led in each treatment arm, and intensive pharmacokinetic studies were performed on about 25 patients per arm at weeks 1 and 12. We estimated the pharmacokinetic parameters of all three drugs by using parametric and nonparametric methods. The mean values of the pharmacokinetic par ameters of zidovudine (clearance [CL]/bioavailability [F], 168 liters/ h; volume of distribution [V]/F, 185 liters; half-life, 0.76 h) and za lcitabine (CL/F, 25 liters/h; V/F, 92.2 liters; half-life, 2.7 h) were similar to those reported previously. For saquinavir, the mean pharma cokinetic parameter estimates using parametric methods were as follows : maximum concentration of drug in serum [C-max], 70.8 ng/ml; time to C-max, 3.11 h; area under the curve, 809 ng . h/ml; CL/F, 989 liters/h ; V/F, 1,503 liters; half-life, 1.38 h. For all three drugs, clearance decreased with age. Weight did not influence the clearance of zidovud ine, but the clearance of zalcitabine and saquinavir increased with we ight. There were so differences in pharmacokinetic parameters between study weeks and arms, suggesting that there is no change in kinetics w ith chronic administration and that there are no significant pharmacok inetic interactions among these three drugs.