title: Pharmacokinetics and pharmacodynamics of ASP2151, a helicase-primase inhibitor, in a murine model of herpes simplex virus infection.
abstract: ASP2151 (amenamevir) is a helicase-primase inhibitor against herpes simplex virus 1 (HSV-1), HSV-2, and varicella zoster virus. Here, to determine and analyze the correlation between the pharmacodynamic (PD) and pharmacokinetic (PK) parameters of ASP2151, we examined the PD profile of ASP2151 using in vitro plaque reduction assay and a murine model of HSV-1 infection. ASP2151 inhibited the in vitro replication of HSV-1 with a mean 50% effective concentration (EC(50)) of 14 ng/ml. In the cutaneously HSV-1-infected mouse model, ASP2151 dose dependently suppressed intradermal HSV-1 growth, with the effect reaching a plateau at a dose of 30 mg/kg of body weight/day. The dose fractionation study showed that intradermal HSV-1 titers were below the detection limit in mice treated with ASP2151 at 100 mg/kg/day divided into two daily doses and at 30 or 100 mg/kg/day divided into three daily doses. The intradermal HSV-1 titer correlated with the maximum concentration of drug in serum (C(max)), the area under the concentration-time curve over 24 h (AUC(24h)), and the time during which the concentration of ASP2151 in plasma was above 100 ng/ml (T(>100)). The continuous infusion of ASP2151 effectively decreased intradermal HSV-1 titers below the limit of detection in mice in which the ASP2151 concentration in plasma reached 79 to 145 ng/ml. Our findings suggest that the antiviral efficacy of ASP2151 is most closely associated with the PK parameter T(>100) in HSV-1-infected mice. Based on these results, we propose that a plasma ASP2151 concentration exceeding 100 ng/ml for 21 to 24 h per day provides the maximum efficacy in HSV-1-infected mice.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Katsumata
authors.forename: Koji
authors.initials: K
authors.lastname: Chono
authors.forename: Kota
authors.initials: K
authors.lastname: Kato
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ohtsu
authors.forename: Shoji
authors.initials: S
authors.lastname: Takakura
authors.forename: Toru
authors.initials: T
authors.lastname: Kontani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019915:DNA Primase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D051379:Mice; D008812:Mice, Hairless; D010069:Oxadiazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000821:virology; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: C568714:ASP2151; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D014764:Viral Proteins; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases