Vol. 30, Issue 12, 1455-1461, December 2002

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Jian-Feng Lu, Terrence F. Blaschke, Charles Flexner, Susan L. Rosenkranz, Lewis B. Sheiner, and AIDS Clinical Trials Group Protocol 378 Investigators

Department of Laboratory Medicine and Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California (J.-F.L., L.B.S.); Department of Experimental and Clinical Pharmacology, Genentech, Inc., South San Francisco, California (J.-F.L.); Department of Medicine, Division of Clinical Pharmacology, Stanford University Medical Center, Stanford, California (T.F.B.); Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland (C.F.); and Statistics and Data Analysis Center, AIDs Clinical Trials Group/Harvard School of Public Health, Boston, Massachusetts (S.L.R.).

Eighteen healthy human immunodeficiency virus-negative subjects participated in an open-label, six-period, incomplete Latin-square crossover pharmacokinetic study. Each subject received two of the three possible pair-wise combinations of single-dose oral ritonavir (R) (400 mg), nelfinavir (N) (750 mg), and saquinavir (S) (800 mg), each pair on three occasions (simultaneous or staggered administration), each occasion at least 2 days after the last. A model-based analysis reveals the following major drug interactions under the conditions of this study: 1) R given simultaneously with S decreases S hepatic intrinsic clearance almost 50-fold relative to that predicted for S given alone and increases its gut bioavailability 90% (but decreases its rate of absorption 40%) relative to when N is given simultaneously; 2) N given simultaneously with S decreases S hepatic intrinsic clearance 10-fold relative to that predicted for S given alone; and 3) R inhibits S hepatic intrinsic clearance even after R plasma levels have become undetectable (>48 h after dosing), implying that R, when used as a pharmacokinetic enhancer, can be dosed less frequently than might be predicted from the duration of detectable systemic concentrations.