This study is aimed to investigate the influence of cenobamate on the activity of CYP3A4/5, CYP2B6, CYP2C19, and CYP2C9 by using drugs recommended by both the FDA and EMA as in vivo probes. In order to avoid a potential pharmacokinetic interaction between the probes, midazolam (CYP3A), warfarin (CYP2C9), and omeprazole (CYP2C19) will be administered together as a validated cocktail and separately from bupropion (CYP2B6) using an adequate washout time period between the 2 assessments. The starting daily dose of cenobamate will be 12.5 mg, which will be administered for 2 weeks. Then, daily cenobamate doses will be increased every 2 weeks to 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg. The CYP probes will be tested before cenobamate administration, at steady state at 100mg/day of cenobamate for midazolam only and finally at steady state at 200mg/day of cenobamate for all CYP probes. The results of this DDI study will provide a basis to make appropriate dose recommendation for a safe use of concomitant drugs with cenobamate using these isoenzymes in their metabolic pathway.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
12.5 mg q.d.(Days 13-26), 25 mg q.d. (Days 27-40), 50 mg q.d. (Days 41-54), 100 mg q.d. (Days 55-70), 150 mg q.d. (Days 71-84), 200 mg q.d. (Days 85-110)
2 mg midazolam syrup (Days 7, 69, 105)
5 mg (Days 7 and 105)
20 mg (Days 7 and 105)
150 mg (Days 1 and 99)
Vince and Associates Clinical Research, Inc.
Overland Park, Kansas, United States
Pharmacokinetic parameters AUC
Will be determined for S- and R-bupropion, total bupropion, midazolam, S-warfarin and R-warfarin, and omeprazole when administered with and without cenobamate at steady state
Time frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)
Pharmacokinetic parameters Cmax
Will be determined for S- and R-bupropion, total bupropion, midazolam, S-warfarin and R-warfarin, and omeprazole when administered with and without cenobamate at steady state
Time frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)
Pharmacokinetic parameters AUC
Will be determined for probe drug metabolites (S,S-hydroxybupropion and R,R-hydroxybupropion, threohydrobupropion, 1-hydroxymidazolam, and 5-OH omeprazole)
Time frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)
Pharmacokinetic parameters Cmax
Will be determined for probe drug metabolites (S,S-hydroxybupropion and R,R-hydroxybupropion, threohydrobupropion, 1-hydroxymidazolam, and 5-OH omeprazole)
Time frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)
Pharmacokinetic parameters AUC (to infinity)
Will be determined for probe drug metabolites (S,S-hydroxybupropion and R,R-hydroxybupropion, threohydrobupropion, 1-hydroxymidazolam, and 5-OH omeprazole)
Time frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)
Pharmacokinetic parameter RAUC (ratio of metabolite to parent)
Will be determined for 5-OH omeprazole/omeprazole, 1-OH midazolam/midazolam, S,S-OH-bupropion/S-bupropion, R,R-OH-bupropion/R-bupropion, total OH-bupropion/total bupropion, threohydrobupropion/R-bupropion
Time frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)
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