PT  - JOURNAL ARTICLE
AU  - Jian-Feng Lu
AU  - Terrence F. Blaschke
AU  - Charles Flexner
AU  - Susan L. Rosenkranz
AU  - Lewis B. Sheiner
AU  - AIDS Clinical Trials Group Protocol 378 Investigators
TI  - Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration
AID  - 10.1124/dmd.30.12.1455
DP  - 2002 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1455--1461
VI  - 30
IP  - 12
4099  - http://dmd.aspetjournals.org/content/30/12/1455.short
4100  - http://dmd.aspetjournals.org/content/30/12/1455.full
SO  - Drug Metab Dispos2002 Dec 01; 30
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