RT Journal Article
SR Electronic
T1 Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1455
OP 1461
DO 10.1124/dmd.30.12.1455
VO 30
IS 12
A1 Lu, Jian-Feng
A1 Blaschke, Terrence F.
A1 Flexner, Charles
A1 Rosenkranz, Susan L.
A1 Sheiner, Lewis B.
A1 AIDS Clinical Trials Group Protocol 378 Investigators
YR 2002
UL http://dmd.aspetjournals.org/content/30/12/1455.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics