Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03234699
Recruitment Status : Completed
First Posted : July 31, 2017
Last Update Posted : August 8, 2017
Sponsor:
Information provided by (Responsible Party):
SK Life Science, Inc.

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.


Condition or disease Intervention/treatment Phase
Healthy Drug: Cenobamate Drug: midazolam Drug: Warfarin Pill Drug: Omeprazole Pill Drug: Bupropion Pill Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description: Open Label
Primary Purpose: Treatment
Official Title: The Effect of Multiple Doses of Cenobamate (YKP3089) on the Single Dose Pharmacokinetics of Cytochrome P450 Substrates (Midazolam, Warfarin, Omeprazole and Bupropion) Administered Orally in an Open-label, One-sequence Study in Healthy Subjects
Actual Study Start Date : February 22, 2017
Actual Primary Completion Date : July 3, 2017
Actual Study Completion Date : July 31, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners

Arm Intervention/treatment
Experimental: Single Group Drug: Cenobamate
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)

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

Drug: Warfarin Pill
5 mg (Days 7 and 105)

Drug: Omeprazole Pill
20 mg (Days 7 and 105)

Drug: Bupropion Pill
150 mg (Days 1 and 99)




Primary Outcome Measures :
  1. Pharmacokinetic parameters AUC [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    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

  2. Pharmacokinetic parameters Cmax [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    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


Secondary Outcome Measures :
  1. Pharmacokinetic parameters AUC [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for probe drug metabolites (S,S-hydroxybupropion and R,R-hydroxybupropion, threohydrobupropion, 1-hydroxymidazolam, and 5-OH omeprazole)

  2. Pharmacokinetic parameters Cmax [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for probe drug metabolites (S,S-hydroxybupropion and R,R-hydroxybupropion, threohydrobupropion, 1-hydroxymidazolam, and 5-OH omeprazole)

  3. Pharmacokinetic parameters AUC (to infinity) [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for probe drug metabolites (S,S-hydroxybupropion and R,R-hydroxybupropion, threohydrobupropion, 1-hydroxymidazolam, and 5-OH omeprazole)

  4. Pharmacokinetic parameter RAUC (ratio of metabolite to parent) [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    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


Other Outcome Measures:
  1. Pharmacokinetic parameters tmax [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for the probe drugs (and metabolites) when administered with or without cenobamate at steady state

  2. Pharmacokinetic parameters Ctz [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for the probe drugs (and metabolites) when administered with or without cenobamate at steady state

  3. Pharmacokinetic parameters tz [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for the probe drugs (and metabolites) when administered with or without cenobamate at steady state

  4. Pharmacokinetic parameters t1/2 [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for the probe drugs (and metabolites) when administered with or without cenobamate at steady state

  5. Pharmacokinetic parameters CL/F [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for the probe drugs (and metabolites) when administered with or without cenobamate at steady state

  6. Pharmacokinetic parameters Vz/F [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for the probe drugs (and metabolites) when administered with or without cenobamate at steady state

  7. Pharmacokinetic parameters Cmin [ Time Frame: bupropion (6 days), midazolam (24 hrs), omeprazole (24 hrs), warfarin (7 days) ]
    Will be determined for the probe drugs (and metabolites) when administered with or without cenobamate at steady state



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male or female subjects between 18 to 50 years of age inclusive
  2. Subject is willing and able to provide informed consent
  3. Body mass index (BMI) within 19.0 kg/m2 and 29.9 kg/m2, inclusive, at screening
  4. Subject is a non- or ex-smoker and has not used any nicotine containing products within 6 months prior to screening
  5. 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
  6. Subjects who are willing and able to comply with the dosing/visit schedule, laboratory tests, pharmacokinetic sampling schedule, and other study procedures
  7. 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:

    1. Diaphragm and spermicide
    2. Condom with spermicide
    3. Sponge and spermicide
    4. Intrauterine device (with or without hormones; placement at least 3 months prior to Screening) in combination with a barrier method
    5. Oral contraceptives, Depo-Provera, Norplant, Patch or intrauterine progesterone contraceptive for at least 90 days prior to screening in combination with a barrier method.
    6. Vasectomized partner (6 months minimum since vasectomy)
    7. Complete abstinence from heterosexual intercourse. However, if the subject becomes sexually active, 1 of the above methods must be utilized.

    If a female of non-childbearing potential - should be surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation at least 6 months prior to Screening) or in a menopausal state (at least 1 year without menses), as confirmed by FSH levels (post menopausal must be confirmed by the subject having a serum follicle stimulating hormone greater than 40mIU/ml at screening)

  8. A female study subject must agree not to donate eggs during the study and for at least 30 days after the last dose of the study medication
  9. A male study subject must agree to use one of the accepted contraceptive regimens during the study and for at least 90 days after the last dose of the study medications;

    1. Abstinence from heterosexual intercourse. However, if the subject becomes sexually active, 1 of the below methods must be utilized
    2. Female partner with hormonal contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch) in combination with a barrier method
    3. Female partner with intrauterine device (with or without hormones) in combination with a barrier method
    4. Female partner with condom with spermicide used by male study subject
    5. Female partner of non-childbearing potential
    6. Female partner with diaphragm with spermicide
    7. Female partner with sponge and spermicide
    8. Male sterilization with absence of sperm in the post vasectomy ejaculate for ≥ 6 months
  10. A male study subject must agree not to donate sperm during the study and for at least 90 days after the last dose of the study medication

Exclusion Criteria:

  1. Females who are breastfeeding
  2. Inadequate venous access
  3. 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
  4. History of 1st degree relative having a serious cutaneous adverse reaction
  5. Current clinically significant rash
  6. 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
  7. 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
  8. 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
  9. Current evidence or history of suicidal tendency, seizures, state of confusion or any other clinically relevant psychiatric disease.
  10. 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
  11. 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
  12. Has current or recent history (within the past year) of alcohol or drug abuse or dependence
  13. Any clinically significant illness in the previous 30 days prior to screening
  14. 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
  15. 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
  16. Clinically-relevant, unusual dietary habits (e.g., vegan, Atkins), dietary restrictions, and/or food allergies
  17. Positive urine screen for alcohol and/or drugs of abuse at screening and at each admission
  18. Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Antibody (HCVAb) at screening
  19. Has been administered any investigational drug 30 days (or 6 times its terminal half-live) prior to Day 1 of this study
  20. Females with a positive pregnancy test at screening, regardless of child-bearing potential prior to Day 1 of this study
  21. Blood donation (excluding plasma donation) of approximately 500 mL within 56 days prior to screening
  22. Subject is unlikely to comply with the study protocol or, in the opinion of the Investigator, would not be a suitable candidate for participation in the trial
  23. Anyone who has previously been exposed to cenobamate (prior to participation in this study)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03234699


Locations
Layout table for location information
United States, Kansas
Vince and Associates Clinical Research, Inc.
Overland Park, Kansas, United States, 66212
Sponsors and Collaborators
SK Life Science, Inc.
Layout table for additonal information
Responsible Party: SK Life Science, Inc.
ClinicalTrials.gov Identifier: NCT03234699    
Other Study ID Numbers: YKP3089C026
First Posted: July 31, 2017    Key Record Dates
Last Update Posted: August 8, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Midazolam
Bupropion
Omeprazole
Warfarin
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anticoagulants
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors
Antidepressive Agents, Second-Generation
Antidepressive Agents
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Dopamine Agents
Cytochrome P-450 CYP2D6 Inhibitors