Amenamevir (formerly ASP2151) induces cytochrome P450 (CYP)2B6 and CYP3A4 and inhibits CYP2C8.  We conducted 2 studies, 1 using montelukast as a probe to assess CYP2C8 and the other bupropion to assess CYP2B6.  The montelukast study examined the effect of amenamevir on the pharmacokinetics of montelukast in 24 healthy men: each subject received montelukast 10 mg alone, followed by montelukast 10 mg with amenamevir 400 mg, or vice versa after a washout period.  In the bupropion study, 24 subjects received a single dose of 150 mg bupropion on days 1, 15, 22, and 29, and repeated once‐daily doses of 400 mg amenamevir on days 6‐15.  Amenamevir increased peak concentration and area under the concentration‐time curve of montelukast by about 22% (ratio 121.7%, 90%CI [114.8, 129.1]; 121% [116.2, 128.4], respectively) with a similar increase in hydroxymontelukast (ratio 121.4%, 90%CI [106.4, 138.5]; 125.6 % [111.3, 141.7]).  Amenamevir reduced peak concentration and area under the concentration‐time curve of bupropion by 16% (84.29%, 90%CI [78.00, 91.10]; 84.07%, 90%CI [78.85, 89.63]), with recovery after 1 week; the pharmacokinetics of the primary metabolite hydroxybupropion was unaffected.  Thus, amenamevir increased plasma concentrations of montelukast and decreased those of bupropion, but it did not do so enough to require dose adjustment of coadministered substrates of either CYP2C8 or CYP2B6.

Amenamevir (formerly ASP2151) is a helicase-primase inhibitor being developed for the treatment of herpesvirus infection. Amenamevir is both a substrate and inducer of cytochrome P450 (CYP) 3A4. Three studies were done in healthy volunteers to investigate potential CYP3A pharmacokinetic interactions with the following drugs: (1) Midazolam (probe substrate for CYP3A): After 10 days' pretreatment with amenamevir 400 mg daily, geometric mean maximum concentration of drug in blood plasma (C ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC ) of midazolam 7.5 mg were about 68% and 51%, respectively, of those after midazolam alone. (2) Cyclosporine (substrate and inhibitor of CYP3A): After 5 days' pretreatment with cyclosporine 100 mg twice daily, geometric mean C of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 66% and 69%, and AUC about 82% and 79%, of those after amenamevir alone. (3) Ritonavir (inhibitor of CYP3A): When given with single doses of ritonavir 600 mg, geometric mean C of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 1.4 and 1.6 times higher, and geometric mean AUC about 2.6 and 3.3 times higher, than after amenamevir alone. Amenamevir has the potential to be involved in CYP3A-mediated pharmacokinetic interactions in clinical practice.

Introduction: Amenamevir (ASP2151), a herpesvirus helicase-primase inhibitor, is currently used for the treatment of herpes zoster in Japan. Amenamevir is mainly metabolized in the liver, and urinary excretion of amenamevir is approximately 10% in healthy adults. The increase of systemic exposure in non-dialysis patients with severe renal impairment was much less than that associated with nucleoside antiviral agents. The aim of this study was to evaluate the pharmacokinetics and dialyzability of a single oral dose (400 mg) of amenamevir in hemodialysis patients. Methods: This was a single-arm, open-label, multicenter clinical pharmacology study. Nine patients aged 20-80 years with end-stage kidney disease and undergoing maintenance hemodialysis three times weekly were enrolled. Pharmacokinetics and dialyzability were investigated by serial collection of blood samples until 48 h post-dose during the study. Results: The maximum plasma concentration and time to reach maximum plasma concentration during 24 h post-dose were 1585 ng/mL and 6.2 h, respectively. The area under the plasma concentration-time curve (AUC) from time zero to 24 h was 23,890 ng h/mL. The median terminal elimination half-life within 24 h before, during, and after hemodialysis was 14.7, 15.2, and 12.4 h, respectively. The AUC in hemodialysis patients was approximately double that in healthy adults. This increase in AUC was much less than that reported in nucleoside antiviral agents. The hemodialysis clearance, elimination fraction percentage, and amount of amenamevir removed were 37.8 mL/min, 28.1%, and 132.0 lg, respectively. The amount of amenamevir removed by hemodialysis was minimal. None of the hemodialysis parameters were associated with serum albumin. This study revealed no clinically relevant safety concerns. Conclusion: There were no clinically relevant safety concerns when 400 mg of amenamevir was administered as a single dose to hemodialysis patients without dose adjustment and/or modification of the dosing schedule.

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In the original article, there is incorrect text has published as ''The hemodialysis clearance, elimination fraction percentage, and amount of amenamevir removed were 37.8 mL/min, 28.1%, and 132.0 lg, respectively''. The correct text is ''The hemodialysis clearance, elimination fraction percentage, and amount of amenamevir removed were 41.4 mL/min, 30.7%, and 7919 lg, respectively''. The incorrect text has published as ''There was no correlation between CL HD and Kt/V (A), but a strong negative correlation between EP and Kt/V (r =-0.75) (C) was found, whereas the amount removed was positively correlated with Kt/V (r = 0.55) (E)''. The correct text is ''There was no correlation between CL HD and Kt/V (A), but a strong negative correlation between EP and Kt/V (r =-0.77) (C) was found, whereas the amount removed was positively correlated with Kt/V (r = 0.58) (E)''.