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Research ArticleArticle

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
Drug Metabolism and Disposition December 2002, 30 (12) 1455-1461; DOI: https://doi.org/10.1124/dmd.30.12.1455
Jian-Feng Lu
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Terrence F. Blaschke
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Charles Flexner
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Susan L. Rosenkranz
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Lewis B. Sheiner
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Abstract

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.

Footnotes

  • Work supported by United States Department of Health and Human Services (National Institutes of Health) Grants AI38858, AI38855, AI27668, and RR00052. Work presented at the American Society for Clinical Pharmacology and Therapeutics 2002 annual meeting, Atlanta, Georgia, March 24-27, 2002.

  • Abbreviations used are::
    PI
    protease inhibitor
    R
    ritonavir
    N
    nelfinavir
    S
    saquinavir
    PK
    pharmacokinetic
    ACTG 378
    adult AIDS clinical trial group study 378
    AUC
    area under the curve
    V
    volume of distribution
    CL
    clearance
    F
    bioavailability
    P-gp
    P-glycoprotein
    • Received March 7, 2002.
    • Accepted August 15, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (12)
Drug Metabolism and Disposition
Vol. 30, Issue 12
1 Dec 2002
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Research ArticleArticle

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
Drug Metabolism and Disposition December 1, 2002, 30 (12) 1455-1461; DOI: https://doi.org/10.1124/dmd.30.12.1455

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Research ArticleArticle

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
Drug Metabolism and Disposition December 1, 2002, 30 (12) 1455-1461; DOI: https://doi.org/10.1124/dmd.30.12.1455
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