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This trial is conducted as a cocktail-study namely an open-label, randomized, two-sequence, two-period crossover, cocktail study where a combination of cocktail-drugs is used to illustrate whether or not, or to what degree dicloxacillin affects the level of activity of the 5 most important CYP enzymes and therefore plays a potentially decisive role in serious drug-drug interactions.
Given knowledge explains dicloxacillin and the drug warfarin to be a potential dangerous drug drug interaction because the effects of warfarin is downregulated to a degree as to where it might cause patients to have thrombotic events.
A potential explanation to this is namely dicloxacillin increases the activity of certain drug metabolising enzymes metabolising warfaring which in turn decreases the concentration of the drug in the blood and the therapeutic effect.
Cocktail study is the golden standard to investigate as to whether there is changes is P450 enzymes as a result of drug-drug interactions.
The cocktail consists of Midazolam, omeprazole, tolbutamide, caffein and dextromethorphan which is well known markers for these enzymes. These markers are safe, have specific (enzyme) metabolism and has been used in several studies with no Serious Adverse reactions reported.
By measuring the Concentration of the drug and its metabolites in plasma / Urine before and after treatment with dicloxacillin we will estimate AUC (area under the curve) and test our hypothesis/primary end point of whether there is change in AUC for Tolbutamide (CYP2C9)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm of study1 | Active Comparator | Dicloxacillin tablets. |
|
| Arm of study 2 | Placebo Comparator | No treatment |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dicloxacillin | Drug | Tablets containing dicloxacillin are taken 500mg 2x 3 times per day, for 10 days. Followed by test-day nr 1 at day 11. Both arms receives both treatments, randomly assigned |
| Measure | Description | Time Frame |
|---|---|---|
| AUC(area under the curve) for tolbutamid (CYP2C9), as a result of dicloxacillin-treatment | AUC measurements giving an estimate of activity og the relevant enzymes. | Pharmacological outcome measures at t=0 predose and postdose; 0.5,1,2,3,4,6,8,10,12,24. |
| Measure | Description | Time Frame |
|---|---|---|
| *AUC(area under the curve) for midazolam (CYP3A4) and dextromethorphan (CYP1A2) omeprazole (CYP2C19) and caffein (CYP1A2) | Pharmacological outcome measures at t=0 predose and postdose; 0.5,1,2,3,4,6,8,10,12,24. | |
| T(max) | The amount of time that the drug is present at the maximum concentration in serum. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Per Damkier, Ph.d. | Assosiated to department of biochemistry and pharmacology at University of southern denmark, Odense | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Klinisk Biokemisk Farmakologi syddansk universitet | Odense | Funen | 5000 | Denmark |
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| ID | Term |
|---|---|
| D004009 | Dicloxacillin |
| D000900 | Anti-Bacterial Agents |
| ID | Term |
|---|---|
| D003023 | Cloxacillin |
| D010068 | Oxacillin |
| D010406 | Penicillins |
| D047090 | beta-Lactams |
| D007769 |
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|
| Placebos | Drug | No drug are taken for 10 days. Non-blinded. Followed by test-day nr 1 at day 11. Both arms receives both treatments, randomly assigned |
|
| Pharmacological outcome measures at t=0 predose and postdose; 0.5,1,2,3,4,6,8,10,12,24. |
| C(max) (peak plasma concentration) | The peak serum concentration of a therapeutic drug. | Pharmacological outcome measures at t=0 predose and postdose; 0.5,1,2,3,4,6,8,10,12,24. |
| Clearance | The volume of plasma from which the drug is completely removed per unit time. Reflects rate of drug elimination divided by plasma concentration. | Pharmacological outcome measures at t=0 predose and postdose; 0.5,1,2,3,4,6,8,10,12,24. |
| Lactams |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013457 | Sulfur Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000890 | Anti-Infective Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |