Dicloxacillin: Clinical Relevance of Drug-drug Interactions by Induction of Drug Metabolism.

Dicloxacillin: Clinical Relevance of Drug-drug Interactions by Induction of Drug Metabolizing Enzymes.

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Dicloxacillin; Drug: Placebos

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Funen
    • Odense, Funen, Denmark, 5000
      • Klinisk Biokemisk Farmakologi syddansk universitet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Are you in a general healthy condition?; questions asked; Are you healthy in general? 2; Do you have any chronic diseases? 3; Are you taking any medications regularly? 4, Are you taking any medications periodically . 5; Are you taking nutrition supplements, "nature-medicine" or over-the-counter drugs
• BMI; range; 18,5-29,9 kg/m2
• eGFR(estimated glomerular filtration rate), ALAT(alanine aminotransferase), bilirubin, hæmoglobin og HbA1c, should be within normal limits or without clinically significantly deviation from these.
• Non-Smoker

Exclusion Criteria:

• Hypersensitivity to applied medications. Known allergy to penicillin or type 1-reaction to cefalosporins.
• Known allergy to sulfonamides
• Clinically relevant intake of receipt-required medication, over-the-counter medication or nutritional supplements.
• Chronic or daily intake of alcohol.
• Participation in other Intervention-studies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm of study1; Dicloxacillin tablets.	Drug: Dicloxacillin; 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; Other Names: antibiotics
Placebo Comparator: Arm of study 2; No treatment	Drug: Placebos; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.

Secondary Outcome Measures

Outcome Measure	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.	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.

Collaborators and Investigators

• Sponsor: Per Damkier
• Investigators: Principal Investigator: Per Damkier, Ph.d., Assosiated to department of biochemistry and pharmacology at University of southern denmark, Odense

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2016
• Primary Completion (Actual): April 5, 2017
• Study Completion (Actual): October 1, 2017

Study Registration Dates

• First Submitted: November 30, 2016
• First Submitted That Met QC Criteria: December 5, 2016
• First Posted (Estimate): December 6, 2016

Study Record Updates

• Last Update Posted (Actual): August 23, 2018
• Last Update Submitted That Met QC Criteria: August 21, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Dicloxacillin
• Other Study ID Numbers: AKF-388

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No