title: Pharmacokinetics-pharmacodynamics of the helicase-primase inhibitor pritelivir following treatment of wild-type or pritelivir-resistant virus infection in a murine herpes simplex virus 1 infection model.
abstract: 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 (EC90) 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 EC90 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.
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Subhajit
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Soumi
authors.initials: S
authors.lastname: Sukla
authors.affiliation: AiCuris GmbH and Co. KG, Wuppertal, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Goldner
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Field
authors.affiliation: AiCuris GmbH and Co. KG, Wuppertal, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kropeit
authors.affiliation: AiCuris GmbH and Co. KG, Wuppertal, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Paulsen
authors.affiliation: AiCuris GmbH and Co. KG, Wuppertal, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Welbers
authors.affiliation: AiCuris GmbH and Co. KG, Wuppertal, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Ruebsamen-Schaeff
authors.affiliation: AiCuris GmbH and Co. KG, Wuppertal, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Zimmermann
authors.affiliation: AiCuris GmbH and Co. KG, Wuppertal, Germany alexander.birkmann@aicuris.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Birkmann
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019915:DNA Primase / Q000037:antagonists & inhibitors*; D053488:DnaB Helicases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017193:Skin Diseases, Viral / Q000188:drug therapy / Q000473:pathology; D013449:Sulfonamides; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011725:Pyridines; D013449:Sulfonamides; D013844:Thiazoles; C453221:pritelivir; D019915:DNA Primase; D053488:DnaB Helicases
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