Amenamevir: Studies of Potential CYP2C8- and CYP2B6-Mediated Pharmacokinetic Interactions With Montelukast and Bupropion in Healthy Volunteers.

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: Studies of Potential CYP3A-Mediated Pharmacokinetic Interactions With Midazolam, Cyclosporine, and Ritonavir in Healthy Volunteers.

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 (Cmax ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC0-∞ ) 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 Cmax of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 66% and 69%, and AUC0-∞ 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 Cmax of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 1.4 and 1.6 times higher, and geometric mean AUC0-∞ 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.