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Pharmacodynamics of cidofovir for vaccinia virus infection in an in vitro hollow-fiber infection model system.
Antimicrob Agents Chemother. 2009 Jan; 53(1):129-35.AA

Abstract

Variola major virus remains a potent weapon of bioterror. There is currently an investigational-new-drug application for cidofovir for the therapy of variola major virus infections. Stittelaar and colleagues compared the levels of effectiveness of postexposure smallpox vaccination (Elstree-RIVM) and antiviral treatment with cidofovir or an acyclic nucleoside phosphonate analogue 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidine (HPMPO-DAPy) 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 (K. J. 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 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 of body weight 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) to cidofovir that will have a robust protective effect will require doses that are 5 to 10 times that currently administered to humans. Such doses may cause nephrotoxicity, and therefore, approaches that include probenecid administration as well as schedules of administration that will help ameliorate the uptake of cidofovir into renal tubular epithelial cells need to be considered when addressing such treatment for people.

Authors+Show Affiliations

Antiviral Pharmacodynamics Laboratory, Emerging Infections and Host Defense Group, Ordway Research Institute, Albany, New York 12208, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18852271

Citation

McSharry, James J., et al. "Pharmacodynamics of Cidofovir for Vaccinia Virus Infection in an in Vitro Hollow-fiber Infection Model System." Antimicrobial Agents and Chemotherapy, vol. 53, no. 1, 2009, pp. 129-35.
McSharry JJ, Deziel MR, Zager K, et al. Pharmacodynamics of cidofovir for vaccinia virus infection in an in vitro hollow-fiber infection model system. Antimicrob Agents Chemother. 2009;53(1):129-35.
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. Antimicrobial Agents and Chemotherapy, 53(1), 129-35. https://doi.org/10.1128/AAC.00708-08
McSharry JJ, et al. Pharmacodynamics of Cidofovir for Vaccinia Virus Infection in an in Vitro Hollow-fiber Infection Model System. Antimicrob Agents Chemother. 2009;53(1):129-35. PubMed PMID: 18852271.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacodynamics of cidofovir for vaccinia virus infection in an in vitro hollow-fiber infection model system. AU - McSharry,James J, AU - Deziel,Mark R, AU - Zager,Kris, AU - Weng,Qingmei, AU - Drusano,George L, Y1 - 2008/10/13/ PY - 2008/10/15/pubmed PY - 2009/4/21/medline PY - 2008/10/15/entrez SP - 129 EP - 35 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 53 IS - 1 N2 - Variola major virus remains a potent weapon of bioterror. There is currently an investigational-new-drug application for cidofovir for the therapy of variola major virus infections. Stittelaar and colleagues compared the levels of effectiveness of postexposure smallpox vaccination (Elstree-RIVM) and antiviral treatment with cidofovir or an acyclic nucleoside phosphonate analogue 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidine (HPMPO-DAPy) 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 (K. J. 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 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 of body weight 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) to cidofovir that will have a robust protective effect will require doses that are 5 to 10 times that currently administered to humans. Such doses may cause nephrotoxicity, and therefore, approaches that include probenecid administration as well as schedules of administration that will help ameliorate the uptake of cidofovir into renal tubular epithelial cells need to be considered when addressing such treatment for people. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/18852271/Pharmacodynamics_of_cidofovir_for_vaccinia_virus_infection_in_an_in_vitro_hollow_fiber_infection_model_system_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=18852271 DB - PRIME DP - Unbound Medicine ER -