Determinants of Warfarin Metabolism

Condition(s) studied

Investigational drug(s) / intervention(s)

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

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

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

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

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

Dicloxacillin: 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.

Study 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.

Eligibility

Primary outcome measure(s)

• 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. — Up to 4 days (96 hours) post drug intake.
  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.
• Losartan oral clearance and the formation clearance of E3174. — Up to 48 hours post drug intake.
  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.
• Flurbiprofen oral clearance. — Up to 36 hours post drug intake.
  Some participant will receive single dose of flurbiprofen 50 mg. Plasma samples will be obtained periodically over 24 hours and urine will be collected.
• Siponimod oral clearance. — Up to 2 weeks following drug intake.
  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.
• Change in S-warfarin and phenytoin pharmacokinetic parameters. — Up to 6 weeks following the administration of the first warfarin single dose.
  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.
• Correlation between CYP2C9 substrate pharmacokinetics and genetic polymorphism. — For up to 5 years following drug intake.
  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.

Trial sites (1)

On this site

More Hadassah Medical Organization trials in Israel

Other trials for the same condition