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

Takada, Akitsugu; Katashima, Masataka; Kaibara, Atsunori; Chono, Koji; Katsumata, Kiyomitsu; Sawamoto, Taiji; Suzuki, Hiroshi; Yano, Yoshitaka

doi:10.1016/j.dmpk.2016.05.005

Cited by 2 publications

(2 citation statements)

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“…In a mouse model of herpes simplex virus type-1 infection, the 50% effective oral doses of amenamevir and valaciclovir were 1.9 mg/kg and 27 mg/kg twice daily, respectively [ 6 ]. The pharmacokinetic-pharmacodynamic relationships of amenamevir in mice, guinea pigs, and humans have been studied extensively [ 7 – 9 ]. According to the Clinical Trials registry, the clinical development of amenamevir has always been associated with a once daily dosing regimen, and its efficacy in phase III study was satisfactory [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Absorption, Distribution, Metabolism, and Excretion of the Novel Helicase-Primase Inhibitor, Amenamevir (ASP2151), in Rodents

Ohtsu

Susaki

Noguchi

2018

Eur J Drug Metab Pharmacokinet

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Background and ObjectivesThe helicase-primase inhibitor amenamevir (ASP2151) is a novel therapeutic agent which has been approved for the treatment of herpes zoster. The present study examined the pharmacokinetic profile of amenamevir in rodents and compared it with data from the literature of past and current established therapies (acyclovir and valaciclovir) to provide additional data to facilitate drug discovery and proper drug use.MethodsIn situ absorption, blood and plasma radioactivity concentrations, tissue distribution, and excretion were determined using liquid scintillation counting. Plasma amenamevir concentrations were measured using a validated chromatographic method. Chemical structures of in vivo metabolites were investigated using liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.ResultsAmenamevir, after single intravenous administration to mice, had an elimination half-life of 2 h. Bioavailability was 40% after single oral administration. In situ absorption data indicated that amenamevir is mainly absorbed in the small intestine. The main component in mouse plasma was amenamevir, accounting for 87.9% of amenamevir-derived components. Our results suggest that the main elimination pathway in mice is oxidative metabolism at a methyl group and a 1,2,3-trisubstituted benzene ring followed by biliary and fecal excretion. Following oral administration of 14C-amenamevir to mice, 100.63% of the dose (10.06% in urine and 90.46% in feces) was excreted by 96 h post-dose.ConclusionsThe underlying mechanism of the improved pharmacokinetic profile of amenamevir was linked to an improved absorption ratio (not hepatic availability) compared to acyclovir, and qualitative differences in elimination (slow metabolism of amenamevir vs rapid urinary excretion of acyclovir/valaciclovir).Electronic supplementary materialThe online version of this article (10.1007/s13318-018-0481-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Absorption, Distribution, Metabolism, and Excretion of the Novel Helicase-Primase Inhibitor, Amenamevir (ASP2151), in Rodents

Ohtsu

Susaki

Noguchi

2018

Eur J Drug Metab Pharmacokinet

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“…Preclinical studies have demonstrated that amenamevir has activity against VZV that is more potent than acyclovir and valacyclovir . The pharmacokinetic‐pharmacodynamic relationships of amenamevir in mice, guinea pigs, and humans have been studied extensively . Phase I studies have shown that amenamevir has less than dose proportional pharmacokinetics in healthy volunteers and is safe and well tolerated at single doses of 5 to 2400 mg or when administered at 300 to 600 mg/day for 7 days .…”

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confidence: 99%

An Open‐Label, Single‐Dose, Human Mass Balance Study of Amenamevir in Healthy Male Adults

Kato

Adel

Meent

et al. 2018

Clinical Pharm in Drug Dev

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Amenamevir is an inhibitor of the helicase‐primase enzyme complex developed for the treatment of varicella zoster virus. This mass balance study investigated the absorption, metabolism, and excretion of a single dose (200 mg) of 14 C‐labeled amenamevir in healthy male volunteers. Blood, urine, and feces samples were collected for up to 8 days after the dose. Safety and tolerability were assessed through voluntary reporting of adverse events, physical examination, and clinical laboratory testing. Amenamevir was rapidly absorbed, with a median time to peak drug concentration of 1.0 to 1.5 hours and a plasma half‐life of 8 to 9 hours. Overall, 95.3% of the administered dose was recovered, with the majority of radiolabeled drug excreted in feces (74.6%) followed by urine (20.6%). The major route of elimination was fecal, with around 70% of the dose excreted as metabolites and <0.1% as the unchanged drug. Metabolic profiling revealed that predominantly radiolabeled amenamevir (80%) and its hydroxyl metabolite R5 (up to 7.1%) were present in plasma. Single‐dose amenamevir was well tolerated; 3 transient and mild adverse events were reported in 3 subjects. Overall, >95% of a single 200‐mg dose of amenamevir was eliminated by 168 hours after the dose, with the major route of elimination being fecal.

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

Cited by 2 publications

References 18 publications

Absorption, Distribution, Metabolism, and Excretion of the Novel Helicase-Primase Inhibitor, Amenamevir (ASP2151), in Rodents

Absorption, Distribution, Metabolism, and Excretion of the Novel Helicase-Primase Inhibitor, Amenamevir (ASP2151), in Rodents

An Open‐Label, Single‐Dose, Human Mass Balance Study of Amenamevir in Healthy Male Adults

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