Healthy
Conditions
Keywords
Healthy Volunteers
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.
Interventions
DRUGWarfarin
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
DRUGPhenytoin
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
DRUGFlurbiprofen
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
DRUGSiponimod
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
DRUGDicloxacillin
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.
Sponsors
Hadassah Medical Organization
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
20 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Age range of 20-50 years old * The absence of significant disease states
Exclusion criteria
* 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Israel
Contacts
CONTACTYoseph Caraco, MD
PRINCIPAL_INVESTIGATORYoseph Caraco, MD
Hadassah Medical Organization
Outcome results
None listed