The Effect of Dicloxacillin on Oral Absorption of Drugs

Study Overview
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Brief Summary
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Worldwide there is an increase in antibiotic resistance which may have fatal long-term consequences. This is due to extensive use and sometimes misuse of antibiotics in the treatment of harmless infections. The primary aim of this study is to investigate if treatment with dicloxacillin can lead to drug-drug interactions through induction of the efflux transporter P-glycoprotein (P-gp). In this study it will also be investigated whether dicloxacillin induces its own metabolism. The hypothesis is based on a previous in vivo study showing that rifampicin induces the intestinal P-gp transporter, through activation of the pregnane X receptor (PXR). Dicloxacillin also activates the PXR receptor in vitro, which could result in an induction of P-gp in vivo. Trial subjects will ingest dicloxacillin for 30 days and at day 10 and 28 ingest dabigatran etexilate to determine if the P-gp transporter has been induced. Plasma and urine will be drawn over 32 hours to determine the concentration of dabigatran. Change in dicloxacillin concentration will also be measured at day 9 and 27 to establish if dicloxacillin induces its own metabolism.

Official Title
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The Effect of Dicloxacillin on Oral Absorption of Drugs

Conditions
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Healthy Volunteers, Drug-drug Interaction

Intervention / Treatment
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* Drug: Dicloxacillin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-55 years The following data must be in the normal range or only clinical insignificantly different from this: Estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALAT), bilirubin, HbA1c, hemoglobin BMI >18.5 and < 30 kg/m2 Bodyweight ≥ 50 kg Non-smoker (abstained from smoking minimum 2 weeks before the first study day and during the trial) Generally healthy Willing to give informed consent Exclusion Criteria: Known sensitivity to any of the used drugs or any excipients listed in section 6.1 in the Summary of Product Characteristics (SmPC) Participating in any other intervention trials Intake of any significant prescription drugs, over-the- counter drugs, herbal drugs, or dietary supplements*. Contraindicated drugs include: Anticoagulants, antiplatelet aggregation medicinal products, ticagrelor, clopidogrel, acetylsalicylic acid, chronic NSAIDs use, amiodarone, verapamil, systemic ketoconazole, clarithromycin, cyclosporin, itraconazole, tacrolimus, posaconazole, dronedarone, glecaprevir/pibrentasvir, quinidine, ritonavir, digoxin, selective serotonin reuptake inhibitors (SSRIs), selective serotonin norephinephrine reuptake inhibitors (SNRIs), pantoprazole, ranitidine, previous use of dicloxacillin or other P-gp or Cytochrome P450 (CYP450) inhibitors/inducers within 4 weeks prior to the start of treatment, probenecid, tetracycline, methotrexate Alcohol abuse or if the Danish Health Authority recommendation regarding alcohol intake has been exceeded 2 weeks before the first study day (men 14 units alcohol/week, women 7 unites alcohol/week) A positive pregnancy test at inclusion screening or any of the study days Known penicillin allergy or reactions against cephalosporins, cephamycin, 1-oxa-ß-lactamer, or carbapenems Women who are breastfeeding Diagnosis of any of the following diseases (current or previous): Mechanical heart valve, congenital or acquired coagulation disorders, thrombocytopenia or functional platelet defects, biopsy within 4 weeks, major trauma, bacterial endocarditis, esophagitis, gastritis, gastroesophageal reflux, active meningitis, encephalitis, intracranial abscess, undergoing surgery, liver disease, history of thrombosis or diagnosed with antiphospholipid syndrome, active cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Baseline<br>The investigators measure the baseline of dicloxacillin and the probe drug dabigatran etexilate. | |
| Experimental: Dicloxacillin treatment<br>The investigators measure the concentration of dicloxacillin after 9 and 27 days and the concentration of dabigatran after 10 and 28 days of continuously taking dicloxacillin. | Drug: Dicloxacillin<br>* Healthy volunteers will take 2x500 mg dicloxacillin 3 times a day for 30 days. The investigators will measure the baseline concentration of dabigatran and dicloxacillin before start of 30 days of dicloxacillin treatment. On day 9 and 27 the investigators will measure the concentration of dicloxacillin. On day 10 and 28 the investigators will measure the concentration of dabigatran.<br>* Other names: Dabigatran etexilate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Area under the curve (AUC) of dabigatran | Change in the activity of the drug transporter P-gp | Baseline and day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in AUC of dabigatran | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in AUC of relevant metabolites of dabigatran etexilate | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in Peak Plasma concentration (Cmax) of dabigatran | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in Cmax of relevant metabolites of dabigatran etexilate | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in Time to reach Cmax (Tmax) of dabigatran | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in Tmax of relevant metabolites of dabigatran etexilate | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in renal clearance (CLr) of dabigatran | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in CLr of relevant metabolites of dabigatran etexilate | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in Elimination half-life (T1/2) of dabigatran | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in T1/2 of relevant metabolites of dabigatran etexilate | Change in the activity of the drug transporter P-gp | Day 10 and 28 | 
| Change in AUC of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in AUC of the metabolite of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in Cmax of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in Cmax of the metabolite of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in Tmax of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in Tmax of the metabolite of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in CLr of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in CLr of the metabolite of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in T1/2 of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in T1/2 of the metabolite of dicloxacillin | Change in the activity of the enzyme responsible for metabolism of dicloxacillin | Day 9 and 27 | 
| Change in biomarkers of drug metabolism enzymes and transporters (DMET) | Change in biomarkers for enzymes and transporters after dicloxacillin treatment | 10 and 28 | 
| Change in exosome-derived biomarkers | Change in exosome-derived biomarkers after dicloxacillin treatment to determine activity of CYP enzymes | 10 and 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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P-gp transporter, Induction of P-gp transporter