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Antimicrobial Agents and Chemotherapy, March 2002, p. 746-754, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.746-754.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Pharmacokinetic Modeling and Simulations of Interaction of Amprenavir and Ritonavir

Mark Sale,* Brian M. Sadler, and Daniel S. Stein

Worldwide Clinical Pharmacology, GlaxoSmithKline Inc., Research Triangle Park, North Carolina

Received 12 January 2001/ Returned for modification 1 August 2001/ Accepted 26 November 2001

Data from three pharmacokinetic drug interaction studies of amprenavir and ritonavir were used to develop a pharmacokinetic interaction model using NONMEM (nonlinear mixed-effect model). A two-compartment linear model with first-order absorption best fit the amprenavir data, while a one-compartment model was used to describe the ritonavir data. The inhibition of elimination of amprenavir by ritonavir was modeled with a maximum effect (Emax) inhibition model and the observed ritonavir concentration. Monte Carlo simulation was then used to predict amprenavir concentrations for various combinations of amprenavir and ritonavir in twice-daily and once-daily dosing regimens. Simulated minimum amprenavir concentrations in plasma (Cmin) in twice-daily and once-daily dosing regimens were compared with protein binding-adjusted 50% inhibitory concentrations (IC50s) for clinical human immunodeficiency virus isolates with different susceptibilities to protease inhibitors (central tendency ratios). The model based on the first two studies predicted the results of the third study. Data from all three studies were then combined to refine the final model. The observed and simulated noncompartmental pharmacokinetic parameters agreed well. From this model, several candidate drug regimens were simulated. These simulations suggest that, in patients who have clinically failed a traditional amprenavir regimen, a regimen of 600 mg of amprenavir with 100 mg of ritonavir twice daily would result in Cmin-to-IC50 ratios similar to that of 1,200 mg of amprenavir twice daily alone for wild-type viruses. In addition, once-daily regimens that result in Cmins above the protein binding-corrected IC50s for wild-type virus are clearly feasible.

* Corresponding author. Mailing address: Division of Clinical Pharmacology, GlaxoSmithKline Inc., Research Triangle Park, NC 27709. Phone: (919) 483-1808. Fax: (919) 305-0092. E-mail: ms93267{at}glaxowellcome.com.

Antimicrobial Agents and Chemotherapy, March 2002, p. 746-754, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.746-754.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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