title: Integrative pharmacokinetic-pharmacodynamic modeling and simulation of amenamevir (ASP2151) for treatment of recurrent genital herpes.
abstract: Amenamevir is a novel drug that targets the viral helicase-primase complex. While dose-dependent efficacy had been observed in non-clinical studies, no clear dose dependence has been observed in humans. We therefore developed a pharmacokinetic/pharmacodynamic (PK/PD) model to explain this inconsistency between species and to clarify the immune-related healing of amenamevir in humans. The model consisted of a non-linear kinetic model for a virtual number of virus plaques as a built-in biomarker. Lesion score was defined as an endpoint of antiviral efficacy, and logit model analysis was applied to the ordered-categorical lesion score. The modeling results suggested the time course profiles of lesion score could be explained with the efficacy terms in the logit model, using change in number of virus plaques as an indicator of the effects of amenamevir and time elapsed as an indicator of the healing of the immune response. In humans, the PD effect was almost dose-independent, and immune-related healing may have been the driving force behind the reduction in lesion scores. Drug efficacy is occasionally masked in diseases healed by the immune response, such as genital herpes. The PK/PD model proposed in the present study must be useful for explanation the PK/PD relationship of such drugs.
authors.affiliation: Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan. Electronic address: akitsugu.takada@astellas.com.
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Takada
authors.affiliation: Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Katashima
authors.affiliation: Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kaibara
authors.affiliation: Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Chono
authors.affiliation: Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan.
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Katsumata
authors.affiliation: Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Sawamoto
authors.affiliation: Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Kyoto Pharmaceutical University, 5 Misasagi-Nakauchicho, Yamashina-ku, Kyoto, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yano
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D006168:Guinea Pigs; D006558:Herpes Genitalis / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010069:Oxadiazoles / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D012008:Recurrence; D018139:Simplexvirus / Q000187:drug effects; D014709:Vero Cells
chemical_list: C568714:ASP2151; D000998:Antiviral Agents; D010069:Oxadiazoles
keywords: Amenamevir; Genital herpes; Modeling and simulation; Pharmacokinetic/pharmacodynamic; Pharmacometrics