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

Abstract

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.

Keywords: amenamevir; bupropion; drug-drug interaction; montelukast.

Figure 1

Bupropion dosing intervals. A, dosing with amenamevir 400 mg once daily; B, dosing with bupropion 150 mg.

Figure 2

Mean montelukast plasma concentration‐time plots (linear and semilogarithmic, N = 24). Values below the limit of quantification were entered as 0 and included in the calculation of means.

Figure 3

Mean methyl‐hydroxymontelukast plasma concentration‐time plots (linear and semilogarithmic, N = 24). Values below the limit of quantification were entered as 0 and included in the calculation of means.

Figure 4

Mean bupropion plasma concentration‐time plots (linear and semilogarithmic, N = 24). Values below the limit of quantification were entered as 0 and included in the calculation of means.

Figure 5

Hydroxybupropion plasma concentration‐time plots (linear and semilogarithmic, N = 24). Values below the limit of quantification were entered as 0 and included in the results.