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.

Pharmacokinetics and Bioequivalence Evaluation of Two Montelukast Sodium Chewable Tablets in Healthy Chinese Volunteers Under Fasted and Fed Conditions

“…7–9 In vitro experiments have demonstrated that montelukast acts as an inhibitor of cytochrome P450 (CYP) 2C8 and as a substrate of CYP 2C8, 2C9, and 3A4. 10–12 …”

Physiologically Based Pharmacokinetic Modeling of Bupropion and Its Metabolites in a CYP2B6 Drug-Drug-Gene Interaction Network

“…Clinical studies of bupropion in single-and multiple-dose regimens were gathered and digitized from the literature [ 27 ]. The collected profiles were divided into a training ( n = 19) and a test dataset ( n = 48), used for model building and model evaluation, respectively [ 3 , 17 , 18 , 19 , 20 , 21 , 22 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Studies in the training dataset were selected to include metabolite concentration-time profiles, a wide dosing range, and different oral formulations.…”

Assessing CYP2C8-Mediated Pharmaceutical Excipient-Drug Interaction Potential: A Case Study of Tween 80 and Cremophor EL−35

“…CYP2C8 is an essential member of the CYP2C family, and it is mainly abundant in the human liver and present at lower levels in the intestine and kidneys. CYP2C8 accounts for approximately 6–7% of hepatic CYP450s and metabolizes more than 100 drugs, including paclitaxel (PTX), rosiglitazone, pioglitazone, repaglinide, imatinib, cerivastatin, enzalutamide, and atorvastatin [ 16 , 17 , 18 , 19 , 20 , 21 ]. Recent studies demonstrated that CYP2C8 participates in the synthesis of epoxyeicosatrienoic acids and reactive oxygen species, which have vasodilative, anti-inflammatory, and anti-atherosclerosis effects in the human cardiovascular system [ 22 ].…”