Determinants of Warfarin Metabolism

NCT00162474 | Recruiting

• 1 other identifier: yc195510-HMO-CTIL
• Study Type: interventional
• Target: 1,000
• Locations: 1 country
• Sites: 1

Brief Summary

The anticoagulant effect of warfarin varies greatly among individuals. Some of this variability is attributed to differences in the activity of CYP2C9, the predominant enzyme involved in the metabolism of S-warfarin. The present study is designed to define the differences in warfarin metabolism among healthy individuals carrying different CYP2C9 genotypes. In addition, the study will define the correlation between the phenytoin metabolic ratio, a marker of CYP2C9 activity in vivo, and warfarin metabolism.

Conditions

Healthy

Keywords

Healthy Volunteers

Outcome Measures

Primary Outcomes (8)

• Warfarin oral clearance

  2 weeks

• Formation clearance of CYP2C9 mediated warfarin metabolites

  2 weeks

• Phenytoin Metabolic Ratio, oral clearance of Phenytoin, Formation clearance of p-HPPH.

  Following single dose administration of Phenytoin 300 mg, at least two blood samples 12 and 24 hours post drug intake will be obtained and urine will be collected for at least 24 hours.

  Up to 4 days (96 hours) post drug intake.

• Losartan oral clearance and the formation clearance of E3174.

  For those participant who receive losartan, blood sample will be collected periodically over 48 hours and urine will be collected for 48 hours. Losartan oral clearance and the formation clearance of E3174 will serve as primary outcomes.

  Up to 48 hours post drug intake.

• Flurbiprofen oral clearance.

  Some participant will receive single dose of flurbiprofen 50 mg. Plasma samples will be obtained periodically over 24 hours and urine will be collected.

  Up to 36 hours post drug intake.

• Siponimod oral clearance.

  Some participants will receive single dose of siponimod 0.25 mg and blood samples will be obtained periodically over the next 2 weeks. Pharmacodynamic response will be evaluated by repeated ECG records and measurement of CBC and potassium.

  Up to 2 weeks following drug intake.

• Change in S-warfarin and phenytoin pharmacokinetic parameters.

  Some patients will receive phenytoin (300 mg) and at least one week later warfarin (20 mg) twice before and after intake of dicloxacillin 500 mg QID for 21 days.

  Up to 6 weeks following the administration of the first warfarin single dose.

• Correlation between CYP2C9 substrate pharmacokinetics and genetic polymorphism.

  Using candidate gene approach, sequencing of relevant regions in chromosome 10 will be conducted. Potential genetic alterations (SNPs, deletions, insertions, p-VNTR) will be correlated with pharmacokinetic parameters of CYP2C9 substrates.

  For up to 5 years following drug intake.

Study Arms (1)

CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod.

EXPERIMENTAL

Each participant may be given at least one of the following CYP2C9 substrates: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.

Drug: Warfarin; Drug: Phenytoin; Drug: Losartan & Hydrochlorothiazide; Drug: Flurbiprofen; Drug: Siponimod; Drug: Dicloxacillin

Interventions

Warfarin DRUG

Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.

CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod.

Phenytoin DRUG

Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.

CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod.

Losartan & Hydrochlorothiazide DRUG

Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.

CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod.

Flurbiprofen DRUG

Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.

CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod.

Siponimod DRUG

Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.

CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod.

Dicloxacillin DRUG

To explore possible effect of dicloxacillin on CYP2C9 activity, some participants will be administered single dose of warfarin and phenytoin before and after intake of dicloxacillin.

CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod.

Eligibility Criteria

• Age: 20 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age range of 20-50 years old
• The absence of significant disease states

You may not qualify if:

• Known hypersensitivity to warfarin or phenytoin
• Known hepersensitivity to penicillins or cephalosporins (Dicloxacillin part)
• The presence of significant disease states
• Regular use of drugs (including birth control pills)

Sponsors & Collaborators

• Hadassah Medical Organization: lead

Study Sites (1)

Hadassah Medical Organization

Jerusalem, Israel

RECRUITING

Related Publications (1)

• Shaul C, Blotnick S, Muszkat M, Bialer M, Caraco Y. Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects. Mol Diagn Ther. 2017 Feb;21(1):75-83. doi: 10.1007/s40291-016-0247-7.

  PMID: 27878474 DERIVED

MeSH Terms

Interventions

Warfarin; Phenytoin; hydrochlorothiazide, losartan drug combination; Flurbiprofen; siponimod; Dicloxacillin

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydantoins; Imidazolidines; Imidazoles; Azoles; Propionates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Cloxacillin; Oxacillin; Penicillins; beta-Lactams; Lactams; Amides; Sulfur Compounds

Study Officials

• Yoseph Caraco, MD

  Hadassah Medical Organization

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yoseph Caraco, MD

CONTACT

00 972 2 6779373; caraco.yoseph@mail.huji.ac.il

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The activity of CYP2C9 will be evaluated using several known substrates such as warfarin, phenytoin, losartan and flurbiprofen. To explore possible interethnic differences, healthy subjects of different ethnic backgrounds will be recruited.

Study Record Dates

• First Submitted: September 11, 2005
• First Posted: September 13, 2005
• Study Start: September 1, 2003
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030
• Last Updated: April 21, 2026

Record last verified: 2026-03

Locations

IL (1)