Assess the Influence of Cenobamate on the PK of Cytochrome P450 (CYP) Probe Drugs As a Means of Predicting Drug-drug Interactions

NCT03234699 | Completed Phase 1 FDA Drug

• 1 other identifier: YKP3089C026
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Healthy

Outcome Measures

Primary Outcomes (2)

• 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

  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

  bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)

Secondary Outcomes (4)

• Pharmacokinetic parameters AUC

  bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)

• Pharmacokinetic parameters Cmax

  bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)

• Pharmacokinetic parameters AUC (to infinity)

  bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)

• Pharmacokinetic parameter RAUC (ratio of metabolite to parent)

  bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)

Other Outcomes (7)

• Pharmacokinetic parameters tmax

  bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)

• Pharmacokinetic parameters Ctz

  bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)

• Pharmacokinetic parameters tz

  bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days)

Study Arms (1)

Single Group

EXPERIMENTAL

Drug: Cenobamate; Drug: midazolam; Drug: Warfarin Pill; Drug: Omeprazole Pill; Drug: Bupropion Pill

Interventions

Cenobamate DRUG

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)

Single Group

midazolam DRUG

2 mg midazolam syrup (Days 7, 69, 105)

Single Group

Warfarin Pill DRUG

5 mg (Days 7 and 105)

Single Group

Omeprazole Pill DRUG

20 mg (Days 7 and 105)

Single Group

Bupropion Pill DRUG

150 mg (Days 1 and 99)

Single Group

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female subjects between 18 to 50 years of age inclusive
• Subject is willing and able to provide informed consent
• Body mass index (BMI) within 19.0 kg/m2 and 29.9 kg/m2, inclusive, at screening
• Subject is a non- or ex-smoker and has not used any nicotine containing products within 6 months prior to screening
• Subjects who are considered generally healthy upon completion of medical history, physical examination, vital signs, screening laboratory results and screening ECG in the opinion of the Investigator
• Subjects who are willing and able to comply with the dosing/visit schedule, laboratory tests, pharmacokinetic sampling schedule, and other study procedures
• A female study subject must meet one of the following criteria:
• If of childbearing potential - agrees to use one of the accepted contraceptive regimens from screening, during the study and for at least 30 days after the last dose of the study medication. Hormonal contraceptives alone will not be considered an adequate method of contraception. An acceptable method of contraception includes one of the following:
• Diaphragm and spermicide
• Condom with spermicide
• Sponge and spermicide
• Intrauterine device (with or without hormones; placement at least 3 months prior to Screening) in combination with a barrier method
• Oral contraceptives, Depo-Provera, Norplant, Patch or intrauterine progesterone contraceptive for at least 90 days prior to screening in combination with a barrier method.
• Vasectomized partner (6 months minimum since vasectomy)
• Complete abstinence from heterosexual intercourse. However, if the subject becomes sexually active, 1 of the above methods must be utilized.

You may not qualify if:

• Females who are breastfeeding
• Inadequate venous access
• History of any drug related hypersensitivity reactions as well as severe hypersensitivity reactions (like angioedema), or DRESS syndrome to any drugs in the opinion of the Investigator
• History of 1st degree relative having a serious cutaneous adverse reaction
• Current clinically significant rash
• Clinically significant history or evidence of gastrointestinal, hepatic, renal, endocrine, pulmonary, neurological, psychiatric, cardiovascular, hematologic, dermatologic, immunologic disease or any other condition known to interfere with the absorption, distribution, metabolism or elimination of drugs that in the opinion of the Investigator would jeopardize the safety of the subject or impact validity of study results
• History of hepatic impairment, cholecystectomy, renal impairment or any other condition known to interfere with the absorption, distribution, metabolism or elimination of orally administered drug
• Presence of observed abnormality (evidenced from physical examination, ECG, vital signs, or laboratory evaluation) that would be clinically significant in the opinion of the Investigator
• Current evidence or history of suicidal tendency, seizures, state of confusion or any other clinically relevant psychiatric disease.
• Subject is at imminent risk of suicide (positive response to question 4 or 5 on the C-SSRS) or had a suicide attempt within 6 months prior to the screening visit
• History of regular alcohol consumption exceeding 7 drinks per week for females and 14 drinks per week for males within 6 months prior to screening
• Has current or recent history (within the past year) of alcohol or drug abuse or dependence
• Any clinically significant illness in the previous 30 days prior to screening
• Use of any enzyme-modifying drugs, including strong inhibitors of CYP enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin and St John's Wort) in the previous 30 days prior to Day 1 of this study
• Use of all drugs associated with DRESS syndrome such as phenobarbital, carbamazepine, phenytoin, lamotrigine, minocycline, sulfonamides, allopurinol, modafinil, dapsone, ziprasidone, vancomycin and olanzapine in the previous 6 months prior to Day 1 of this study

Sponsors & Collaborators

• SK Life Science, Inc.: lead

Study Sites (1)

Vince and Associates Clinical Research, Inc.

Overland Park, Kansas, 66212, United States

Location

MeSH Terms

Interventions

Cenobamate; Midazolam; Warfarin; Omeprazole; Bupropion

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Benzimidazoles; Propiophenones; Ketones

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: Open Label
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 17, 2017
• First Posted: July 31, 2017
• Study Start: February 22, 2017
• Primary Completion: July 3, 2017
• Study Completion: July 31, 2017
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)