In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 58, No. 7 ( 2014-07), p. 3843-3852
Kurzfassung:
Herpes simplex virus (HSV) infections can cause considerable morbidity. Transmission of HSV-2 has become a major health concern, since it has been shown to promote transmission of other sexually transmitted diseases. Pritelivir (AIC316, BAY 57-1293) belongs to a new class of HSV antiviral compounds, the helicase-primase inhibitors, which have a mode of action that is distinct from that of antiviral nucleoside analogues currently in clinical use. Analysis of pharmacokinetic-pharmacodynamic parameters is a useful tool for the selection of appropriate doses in clinical trials, especially for compounds belonging to new classes for which no or only limited data on therapeutic profiles are available. For this purpose, the effective dose of pritelivir was determined in a comprehensive mouse model of HSV infection. Corresponding plasma concentrations were measured, and exposures were compared with efficacious concentrations derived from cell cultures. The administration of pritelivir at 10 mg/kg of body weight once daily for 4 days completely suppressed any signs of HSV infection in the animals. Associated plasma concentrations adjusted for protein binding stayed above the cell culture 90% effective concentration (EC 90 ) for HSV-1 for almost the entire dosing interval. Interestingly, by increasing the dose 6-fold and prolonging the treatment duration to 8 days, it was possible to treat mice infected with an approximately 30-fold pritelivir-resistant but fully pathogenic HSV-1 virus. Corresponding plasma concentrations exceeded the EC 90 of this mutant for 〈 8 h, indicating that even suboptimal exposure to pritelivir is sufficient to achieve antiviral efficacy, possibly augmented by other factors such as the immune system.
Materialart:
Online-Ressource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.02641-14
Sprache:
Englisch
Verlag:
American Society for Microbiology
Publikationsdatum:
2014
ZDB Id:
1496156-8
SSG:
12
SSG:
15,3
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