The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs

• Published in: Antiviral research 2005, Vol.65 (1), p.35-43
• Main Authors: Schleiss, Mark R., Bernstein, David I., McVoy, Michael A., Stroup, Greg, Bravo, Fernando, Creasy, Blaine, McGregor, Alistair, Henninger, Kristin, Hallenberger, Sabine
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Antiviral therapy; BAY 38-4766; Biological and medical sciences; CMV infection; Cytomegalovirus; Cytomegalovirus - drug effects; Cytomegalovirus - genetics; Cytomegalovirus Infections - drug therapy; Cytomegalovirus Infections - mortality; Cytomegalovirus Infections - virology; Disease Models, Animal; Drug Resistance, Viral; Guinea pig; Guinea pig cytomegalovirus; Guinea Pigs; Immunocompromised animal model; Immunocompromised Host; Medical sciences; Naphthalenesulfonates - adverse effects; Naphthalenesulfonates - pharmacokinetics; Naphthalenesulfonates - therapeutic use; Pharmacology. Drug treatments; Placenta; Real-time PCR; Treatment Outcome
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2004.09.004

New antiviral drugs are needed for the treatment of cytomegalovirus (CMV) infections, particularly in immunocompromised patients. These studies evaluated the in vitro and in vivo activity of the non-nucleosidic CMV inhibitor, BAY 38-4766, against guinea pig cytomegalovirus (GPCMV). Plaque reduction assays indicated that BAY 38-4766 was active against GPCMV, with an IC 50 of 0.5 μM. Yield reduction assays demonstrated an ED 90 and ED 99 of 0.4 and 0.6 μM, respectively, of BAY 38-4766 against GPCMV. Guinea pigs tolerated oral administration of 50 mg/kg/day of BAY 38-4766 without evidence of biochemical or hematologic toxicity. Plasma concentrations of BAY 38-4766 were high following oral dosing, with a mean peak level at 1-h post-dose of 26.7 mg/ml ( n = 6; range, 17.8–35.4). Treatment with BAY 38-4766 reduced both viremia and DNAemia, as determined by a real-time PCR assay, following GPCMV infection of cyclophosphamide-immunosuppressed strain 2 guinea pigs ( p < 0.05, Mann–Whitney test). BAY 38-4766 also reduced mortality following lethal GPCMV challenge in immunosuppressed Hartley guinea pigs, from 83% (20/24) in placebo-treated guinea pigs, to 17% (4/24) in BAY 38-4766-treated animals ( p < 0.0001, Fisher's exact test). Mortality differences were accompanied by reduction in DNAemia in Hartley guinea pigs. Based upon its favorable safety, pharmacokinetic, and therapeutic profiles, BAY 38-4766 warrants further investigation in the GPCMV model.