Pharmacodynamics of Cidofovir for Vaccinia Virus Infection in an In Vitro Hollow-Fiber Infection Model System

Abstract

). 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.With the threat of terrorist attacks in the United States and abroad, the accidental or intentional exposure to category A pathogens is a real possibility. Of the many bacterial and viral agents of bioterrorism, Variola major virus, the cause of smallpox, is of greatest concern because it can be produced in large quantities, is very stable, easily aerosolized, and can kill up to 30% of unvaccinated people who are infected with the virus (27). A live attenuated vaccine, Dryvax, for the prevention of smallpox is available and was used successfully by the World Health Organization to wipe out the natural disease (5, 42). However, in rare cases, the vaccine had serious side effects, particularly in immunocompromised recipients, leading to the cessation of routine smallpox vaccination programs. Since universal vaccination for the prevention of smallpox was discontinued in the 1970s, large segments of the world's population are susceptible to infection with poxviruses. Despite a large effort to produce effective and safer vaccines to protect the world's population against infection with poxviruses, at present, no safer smallpox vaccine has been licensed for use in humans.In the absence of safe vaccines for smallpox, there is an ongoing search for safe and effective chemotherapeutic agents for the prevention and therapy of smallpox. This effort has identified several antiviral compounds that show in vitro and in vivo efficacy for poxvirus infections (1, 3, 4, 6, 7, 14-16, 21-23, 25-26, 28, 30-34, 36-41, 45). One of these compounds, cidofovir, is approved for treatment of cytomegalovirus retinitis in immunocompromised individuals (11). A recent publication suggests that cidofovir and an experimental nucleoside phosphonate, 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidine (HPMPO-DAPy), were more effective than an acute postexposure vaccination regimen with the Elstree strain of vaccinia virus (VV) for ...

Prediction of the Pharmacodynamically Linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow-Fiber Infection Model System

“…1). The use of the system with viruses has been previously described (26). For our studies with oseltamivir carboxylate and the A/Sydney/5/97 R292 strain of influenza virus, we used 4300-C2011 hollow-fiber cartridges (FiberCell Systems, Inc., Frederick, MD) containing high-molecular-cutoff (average pore size, 20 kDa) polysulfone fibers.…”

Comparative In Vitro and In Vivo Efficacies of Human Simulated Doses of Ceftazidime and Ceftazidime-Avibactam against Pseudomonas aeruginosa

“…The pharmacological activity of the selected human dose of 2 g/0.5 g of ceftazidime-avibactam was tested in the hollowfiber system against seven strains of P. aeruginosa with ceftazidimeavibactam MICs of 4 (n ϭ 3) and 8 (n ϭ 4) mg/liter. The schematic of the hollow-fiber system has been described in detail elsewhere (2,18,21). For these studies, cellulosic cartridges from FiberCell Systems, Inc. (Frederick, MD), with a molecular mass cutoff of 20 kDa, were inoculated with logphase cultures of the test microorganism.…”

Evaluation of inhaled cidofovir as postexposure prophylactic in an aerosol rabbitpox model

“…A fivefold lower concentration of drug delivered directly to the lung achieved protection against lethality at the same level as the IV-Cr treatment. It has been suggested that the currently accepted dose for the treatment of cytomegalovirus (5 mg/kg) in human patients would necessitate a 5 to 10 fold increase in order to provide the adequate protection for people exposed to Variola virus (McSharry et al , 2009). The nephrotoxic effects of the 5 mg/kg dose have already been documented (Lalezari et al , 1997), increasing dosage could further increase nephrotoxicity.…”