PHARMACOKINETIC INTERACTIONS BETWEEN 2 HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE INHIBITORS, RITONAVIR AND SAQUINAVIR

Objective: To assess the pharmacokinetic interaction between ritonavir and saquinavir, Methods: Ritonavir and saquinavir were administered i n single doses to six groups of healthy volunteers in a two-way (saqui navir alone and ritonavir plus saquinavir for groups I through V) and a three-way (ritonavir alone, saquinavir alone, and ritonavir plus saq uinavir for group VI) crossover manner with the following doses: group I, 200 mg saquinavir and 300 mg ritonavir; group II, 200 mg saquinavi r and 600 mg ritonavir; group III, 400 mg saquinavir and 300 mg ritona vir; group IV, 400 mg saquinavir and 600 mg ritonavir; group V, 600 mg saquinavir and 200 mg ritornavir; group VI, 600 mg saquinavir and 600 mg ritonavir, Results: Coadministration of ritonavir markedly increas ed the area under the plasma concentration-time curve (AUC) and peak c oncentration of saquinavir (>50-fold and 22-fold, respectively). For a constant ritonavir dose, the pharmacokinetics of saquinavir were rela tively proportional to dose. For a constant saquinavir dose, the incre ase in saquinavir concentration tended to be less than proportional to ritonavir dose. Ritonavir reduced intersubject variability in the saq uinavir AUC from 60% to 28%, The in vivo inhibition constant was 0.025 +/- 0.020 mu g/ml with noncompartmental estimation and 0.0164 +/- 0.0 004 mu g/ml with nonlinear mixed-effects model compartmental analysis, Saquinavir showed no clinically significant effect on the pharmacokin etics of ritonavir (+6.4% in AUG). The regimens were well tolerated. C onclusions: The large effect of ritonavir on the pharmacokinetics of s aquinavir is consistent with a large reduction of saquinavir first-pas s metabolism and postabsorptive clearance. Given the limited bioavaila bility of saquinavir given in the hard gelatin capsule formulation, th is drug interaction is expected to have implications in the use of pro tease inhibitors in the management of human immunodeficiency virus inf ection.