AAC Accepts, published online ahead of print on 13 October 2008

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

 Previous Article  |  Next Article 

Antimicrob. Agents Chemother. doi:10.1128/AAC.00708-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Pharmacodynamics of Cidofovir for Vaccinia Virus Infection in an in vitro Hollow Fiber Infection Model (HFIM) System

James J. McSharry, Mark R. Deziel, Kris Zager, Qingmei Weng, and George L. Drusano^*

Antiviral Pharmacodynamics Laboratory, Emerging Infections and Host Defense Group, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208

^* To whom correspondence should be addressed. Email: GDrusano{at}ordwayresearch.org.

Variola major virus remains a potent weapon of bioterror. Cidofovir currently has an Investigational New Drug (IND) application for the therapy of Variola major virus infections. Stittelaar and colleagues compared the effectiveness of post-exposure smallpox vaccination (Elstree-RIVM) and antiviral treatment with cidofovir or an acyclic nucleoside phosphonate analogue (HPMPO-DAYp) after lethal intratracheal infection of cynomolgus monkeys with monkeypox virus, a Variola virus surrogate. Their results demonstrated that either compound was more effective than vaccination with the Ellstree vaccine (Stittelaar et al., Nature 439:745-748, 2006). An unanswered question is how to translate this information into therapy for poxvirus infections in people. In a proof of principle study, we used a novel in vitro hollow fiber infection model (HFIM) system to determine the pharmacodynamics of vaccinia virus-infection of Hela-S3 cells treated with cidofovir. Our results demonstrate that the currently licensed dose of cidofovir of 5 mg/kg weekly with probenecid (which ameliorates nephrotoxicity) is unlikely to provide protection for patients intentionally exposed to Variola major virus. We further demonstrate that the antiviral effect is independent of the schedule of drug administration. Exposures (Area Under the concentration-time Curve or AUC) to cidofovir that will have a robust protective effect will require doses that are 5-10 times that currently administered to man. Such doses may cause nephrotoxicity and, therefore, approaches that include probenecid administration as well as schedules of administration that will help ameliorate uptake of cidofovir into renal tubular epithelial cells need to be considered when addressing such treatment for people.

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]