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.

Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase

“…Amenamevir was initially developed by Astellas Pharma Inc. for treating drug-resistant HSV-1 and VZV infections (130–134). Its development was halted in 2010 due to toxicity observed during a Phase I study (NCT00870441).…”

Integrative pharmacokinetic–pharmacodynamic modeling and simulation of amenamevir (ASP2151) for treatment of recurrent genital herpes

“…amount of virus plaques and the 409 elapsed time. Our previous study regarding virus plaques showed that the continual exposure 410 of amenamevir above a certain concentration is necessary to prevent the virus re-production 411 [5], and this was confirmed by another study with multiple dose design which is usually used 412 in the antibiotics area [17]. During the clinical development of amenamevir, the value for 413 EC 50 obtained in the non-clinical studies could be directly extrapolated into the clinical study 414 and is used for the dose rationale [5,6] As results, the non-clinical EC 50 without a cure effect 415 was under-estimated, we were unable to detect a clear dose relationship in the clinical study.…”

“…The observed plaque counts versus amenamevir concentration are 343 plotted with the 95% prediction interval in Figure 4. The estimated EC 50 was 127 ng/mL, 344 which is a little smaller than the in vitro expected effective concentration of 200 ng/mL [5]. Table 2, 364 and no 95% confidence intervals (CIs) for any fixed effects included 0, indicating that all 365 parameters were significant.…”

“…This The antiviral activities of amenamevir against HSVs were tested using a plaque reduction 125 assay, as described previously [4,5] to determine the concentration and time dependent 126 effects of amenamevir. Briefly, HEF cells were seeded into multiwell plates and incubated 127 until they formed a monolayer.…”

The DNA helicase–primase complex as a target for herpes viral infection

“…ASP2151 (Amenamevir, Figure 3) inhibits the single-stranded DNA-dependent ATPase, helicase and primase activities associated with the HSV-1 helicase–primase complex and exhibits antiviral activity against HSV-1, HSV-2 and VZV [111]. In mice oral ASP2151 was more effective than oral valacyclovir at reducing intradermal HSV-1 titers and for treating herpes simplex keratitis [112,113]. A Phase II study showed that ASP2151 was a safe and effective treatment for genital HSV infection [114,115]; however, another recent Phase I clinical trial was discontinued because of adverse events [116].…”