This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Preston, S. L.
Right arrow Articles by Drusano, G. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Preston, S. L.
Right arrow Articles by Drusano, G. L.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, November 2003, p. 3393-3399, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3393-3399.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vitro-In Vivo Model for Evaluating the Antiviral Activity of Amprenavir in Combination with Ritonavir Administered at 600 and 100 Milligrams, Respectively, Every 12 Hours

Sandra L. Preston,1 Peter J. Piliero,1 John A. Bilello,2 Daniel S. Stein,2 William T. Symonds,2 and George L. Drusano1*

Division of Clinical Pharmacology, Clinical Research Initiative, Albany Medical College, Albany, New York,1 Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Research Triangle Park, North Carolina2

Received 27 November 2002/ Returned for modification 17 May 2003/ Accepted 15 July 2003

The study objective was to evaluate the pharmacodynamics of amprenavir in an in vitro system, develop an exposure target for maximal viral suppression, and determine the likelihood of target attainment based on the pharmacokinetics of amprenavir and ritonavir in human immunodeficiency virus (HIV)-infected patients. Population pharmacokinetic data were obtained from 13 HIV-infected patients receiving amprenavir and ritonavir in doses of 600 and 100 mg, respectively, every 12 h. A 2,500-subject Monte Carlo simulation was performed. Target attainment was also estimated for a target derived from clinical data. Maximal viral suppression (in vitro) was achieved when amprenavir free-drug concentrations remained greater than four times the 50% effective concentration (EC50) for 80% of the dosing interval. At an amprenavir EC50 of 0.03 µM, the likelihood of target attainment is 97.4%. For reduced-susceptibility isolates for which the EC50s are 0.05 and 0.08 µM, target attainment is 91.0 and 75.8%, respectively. For the clinical target of a trough concentration/EC50 ratio of 5, the target attainment rates were similar. Treatment with amprenavir and ritonavir at doses of 600 and 100 mg, respectively, twice a day provides excellent suppression of wild-type isolates and reduced-susceptibility isolates up to an EC50 of 0.05 µM. Even at 0.12 µM, target attainment likelihood exceeds 50%, making this an option for patients with extensive exposure to protease inhibitors when this treatment is used with additional active antiretroviral agents.

* Corresponding author. Mailing address: Division of Clinical Pharmacology, Clinical Research Institute, Albany Medical College, MC 142, 47 New Scotland Ave. Albany, NY 12208. Phone: (518) 262-6330. Fax: (518) 262-6333. E-mail: GLDRUSANO{at}AOL.COM.

Antimicrobial Agents and Chemotherapy, November 2003, p. 3393-3399, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3393-3399.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • McSharry, J. J., Weng, Q., Brown, A., Kulawy, R., Drusano, G. L. (2009). Prediction of the Pharmacodynamically Linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow-Fiber Infection Model System. Antimicrob. Agents Chemother. 53: 2375-2381 [Abstract] [Full Text]  
  • McSharry, J. J., Deziel, M. R., Zager, K., Weng, Q., Drusano, G. L. (2009). Pharmacodynamics of Cidofovir for Vaccinia Virus Infection in an In Vitro Hollow-Fiber Infection Model System. Antimicrob. Agents Chemother. 53: 129-135 [Abstract] [Full Text]  
  • Louie, A., Deziel, M., Liu, W., Drusano, M. F., Gumbo, T., Drusano, G. L. (2005). Pharmacodynamics of Caspofungin in a Murine Model of Systemic Candidiasis: Importance of Persistence of Caspofungin in Tissues to Understanding Drug Activity. Antimicrob. Agents Chemother. 49: 5058-5068 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»