Efficacy of ASP2151, a helicase–primase inhibitor, against thymidine kinase-deficient herpes simplex virus type 2 infection in vitro and in vivo

Himaki, Takehiro; Masui, Yumi; Chono, Koji; Daikoku, Tohru; Takemoto, Masaya; Haixia, Bo; Okuda, Tomoko; Suzuki, Hiroshi; Shiraki, Kimíyasu

doi:10.1016/j.antiviral.2011.11.015

Cited by 19 publications

(19 citation statements)

References 29 publications

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“…Oral lipid‐ester formulations of cidofovir (CMX‐001) and helicase‐primase inhibitors (e.g. ASP2151) are currently in later stages of development and may be available in the near future . To the extent possible, doses of immunosuppressive therapy should be reduced in patients with acyclovir resistant disease (Grade III).…”

Section: Herpes Simplex Virus (Hsv) 1 Andmentioning

confidence: 99%

Herpes Simplex Virus in Solid Organ Transplantation

Wilck

Zuckerman

2013

American Journal of Transplantation

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Section: Herpes Simplex Virus (Hsv) 1 Andmentioning

confidence: 99%

Herpes Simplex Virus in Solid Organ Transplantation

Wilck

Zuckerman

2013

American Journal of Transplantation

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“…Amenamevir (ASP2151) is a nonnucleoside antiherpes compound developed for the treatment of VZV infections. Preclinical studies have indicated that amenamevir targets the viral helicase–primase complex, which is essential for viral DNA replication [ 7 , 8 ]. The main elimination pathway of amenamevir was hepatic metabolism in animal studies (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Evaluation of the Interactions of Amenamevir (ASP2151) with Ketoconazole, Rifampicin, Midazolam, and Warfarin in Healthy Adults

et al. 2017

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IntroductionAmenamevir is a nonnucleoside antiherpes virus compound available for treating herpes zoster infections. Four studies aimed to determine any potential interactions between amenamevir and ketoconazole, rifampicin, midazolam, or warfarin in healthy male participants.MethodsTwo studies were open-label studies that evaluated the effects of multiple doses of ketoconazole (400 mg) and rifampicin (600 mg) on the pharmacokinetics of a single oral dose of amenamevir. The other two studies were randomized, double-blind, parallel-group studies that evaluated the effects of multiple doses of amenamevir on the pharmacokinetics of a single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to occur if the 90% confidence interval (CI) of the least squares geometric mean ratio (GMR) of amenamevir to the comparator was outside the prespecified interval of 0.80–1.25.ResultsInteractions were observed between amenamevir and ketoconazole, rifampicin, and midazolam, but not between amenamevir and warfarin. After a single 400-mg dose of amenamevir, the GMRs of amenamevir plus ketoconazole or rifampicin versus amenamevir alone for C max and the area under the plasma concentration–time curve from time zero to infinity (AUCinf) were 1.30 (90% CI 1.17–1.45) and 2.58 (90% CI 2.32–2.87), respectively, for ketoconazole and 0.42 (90% CI 0.37–0.49) and 0.17 (90% CI 0.15–0.19), respectively, for rifampicin. Following multiple doses of amenamevir (400 mg), the GMRs of midazolam plus amenamevir versus midazolam alone for AUCinf and C max were 0.53 (90% CI 0.47–0.61) and 0.63 (90% CI 0.50–0.80), respectively. After a single dose of warfarin, the (S)-warfarin and (R)-warfarin mean C max increased and mean AUCinf decreased in the presence of amenamevir; however, the 90% CIs of the GMRs for these parameters remained within the predefined limits.ConclusionThese findings confirm that amenamevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, and (as a cytochrome P450 3A4 inducer) can interact with midazolam; however, no interaction between amenamevir and (S)-warfarin was observed, indicating that amenamevir is not an inducer of cytochrome P450 2C9.FundingAstellas Pharma.Trial registrationEudraCT2007-002227-33 (study 15L-CL-008), EudraCT2007-002228-14 (study 15L-CL-009), EudraCT2007-002761-13 (study 15L-CL-010), and EudraCT2007-002779-14 (study 15L-CL-018).

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“…A few potent antivirals are non-nucleoside analogs (Coen and Richman 2007; Himaki et al 2012). Compounds such as plant extracts have been reported to exhibit anti-herpetic activity in vitro and some in vivo (Nakama et al 2012).…”

Section: Discussionmentioning

confidence: 99%

The antimicrobial agent C31G is effective for therapy for HSV-1 ocular keratitis in the rabbit eye model

et al. 2013

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1. Summary The amphoteric C31G solution contains equimolar alkyl dimethlyglycine and alkyl dimethyl amine oxide buffered with citric acid. C31G acts as a broad spectrum antiviral and an antibacterial. No previous in vivo studies have been done to test C31G in an animal model of HSV-1 ocular keratitis. We assessed the anti-herpetic activity of C31G in the rabbit eye model using three treatment groups: (1) 1% trifluorothymidine (TFT); (2) 0.25% C31G plus 0.5% hydroxypropyl methylcellulose (HPMC); and (3) 0.5% HPMC. Scarified rabbit corneas were inoculated with the HSV-1 strain McKrae. On post inoculation (PI) day 3, rabbits were placed in three balanced groups based on slit-lamp examination (SLE) scores. Treatment began on PI day 3, five times a day for five consecutive days. In addition to the daily, masked SLE scoring, the eyes were assessed daily for stromal opacity, scleral inflammation, neovascularization, eyelid inflammation, inflammatory discharge, and epiphora. C31G and TFT were very effective in reducing the lesions and pathogenesis associated with HSV-1 ocular keratitis. The vehicle control SLE scores were significantly higher, proving that the vehicle did not effectively treat HSV-1 keratitis. C31G has valuable potential to treat herpetic keratitis as well as other herpetic topical lesions in humans.

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Efficacy of ASP2151, a helicase–primase inhibitor, against thymidine kinase-deficient herpes simplex virus type 2 infection in vitro and in vivo

Cited by 19 publications

References 29 publications

Herpes Simplex Virus in Solid Organ Transplantation

Herpes Simplex Virus in Solid Organ Transplantation

Pharmacokinetic Evaluation of the Interactions of Amenamevir (ASP2151) with Ketoconazole, Rifampicin, Midazolam, and Warfarin in Healthy Adults

The antimicrobial agent C31G is effective for therapy for HSV-1 ocular keratitis in the rabbit eye model

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