TY - JOUR
T1 - Model-based analysis of the pharmacokinetic interactions between ritonavir, nelfinavir, and saquinavir after simultaneous and staggered oral administration
AU - Lu, Jian Feng
AU - Blaschke, Terrence F.
AU - Flexner, Chables
AU - Rosenkranz, Susan L.
AU - Sheiner, Lewis B.
PY - 2002/12/1
Y1 - 2002/12/1
N2 - 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.
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.
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U2 - 10.1124/dmd.30.12.1455
DO - 10.1124/dmd.30.12.1455
M3 - Article
C2 - 12433819
AN - SCOPUS:1842833729
SN - 0090-9556
VL - 30
SP - 1455
EP - 1461
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 12
ER -