Pharmacokinetics and Pharmacodynamics of ASP2151, a Helicase-Primase Inhibitor, in a Murine Model of Herpes Simplex Virus Infection
| Autor: | Toru Kontani, Yoshiaki Ohtsu, Kota Kato, Koji Chono, Kiyomitsu Katsumata, Shoji Takakura, Hiroshi Suzuki |
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| Rok vydání: | 2013 |
| Předmět: |
viruses
DNA Primase Herpesvirus 1 Human Viral Plaque Assay Biology Pharmacology Virus Replication medicine.disease_cause Antiviral Agents Drug Administration Schedule Mice Viral Proteins Pharmacokinetics medicine Animals Pharmacology (medical) Amenamevir Enzyme Inhibitors Skin Mice Hairless Oxadiazoles Dose-Response Relationship Drug DNA Helicases Varicella zoster virus Dose fractionation Herpes Simplex Titer Dose–response relationship Infectious Diseases Herpes simplex virus Area Under Curve Pharmacodynamics Female |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 57:1339-1346 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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