EXPOSURE-RESPONSE RELATIONSHIPS FOR SAQUINAVIR, ZIDOVUDINE, AND ZALCITABINE IN COMBINATION THERAPY

The relationship of CD4(+) cell response, level of RNA in plasma, and quantitative peripheral blood mononuclear cell (PBMC) titer to apparen t drug exposure was investigated by using data from AIDS Clinical Tria l Group protocol 229, a multicenter randomized study. Patients receive d either saquinavir, zalcitabine, or a combination of both, along with open-label zidovudine. Approximately 100 patients were enrolled in ea ch arm, and the primary study duration was 24 weeks. Individual drug e xposure, the area under the concentration-time curve, was estimated by using population-based pharmacokinetic methods. Response was defined as the maximum increase in CD4(+) cell count or the maximum decrease i n RNA in plasma or PBMC titer adjusted for baseline CD4(+) cell count, RNA in plasma, and PBMC titer, respectively. Regression of responses on exposure demonstrated an exposure effect for saquinavir which was s ignificant for the maximum increase in CD4(+) cell count and the decre ase in RNA in plasma. For the PBMC titer, no significant relationship could be demonstrated but the results suggested a trend similar to tha t of the other response variables. For all three response variables, t he slope of the saquinavir exposure response was greater with the trip le combination (saquinavir, zidovudine, and zalcitabine) than with the combination of saquinavir and zidovudine, suggesting possible synergi sm between saquinavir and zalcitabine.