Clinical trial NCT05073627: The Effect of Dicloxacillin on Oral Absorption of Drugs
Official title: The Effect of Dicloxacillin on Oral Absorption of Drugs
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Drug-drug Interaction
Keywords: P-gp transporter, Induction of P-gp transporter
Lead sponsor: University of Southern Denmark
Sponsor class: OTHER
First posted: 2021-10-11
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Change in Area under the curve (AUC) of dabigatran
timeFrame: Baseline and day 28
Secondary outcomes:
measure: Change in AUC of dabigatran
timeFrame: Day 10 and 28
measure: Change in AUC of relevant metabolites of dabigatran etexilate
timeFrame: Day 10 and 28
measure: Change in Peak Plasma concentration (Cmax) of dabigatran
timeFrame: Day 10 and 28
measure: Change in Cmax of relevant metabolites of dabigatran etexilate
timeFrame: Day 10 and 28
measure: Change in Time to reach Cmax (Tmax) of dabigatran
timeFrame: Day 10 and 28
measure: Change in Tmax of relevant metabolites of dabigatran etexilate
timeFrame: Day 10 and 28
measure: Change in renal clearance (CLr) of dabigatran
timeFrame: Day 10 and 28
measure: Change in CLr of relevant metabolites of dabigatran etexilate
timeFrame: Day 10 and 28
measure: Change in Elimination half-life (T1/2) of dabigatran
timeFrame: Day 10 and 28
measure: Change in T1/2 of relevant metabolites of dabigatran etexilate
timeFrame: Day 10 and 28
measure: Change in AUC of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in AUC of the metabolite of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in Cmax of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in Cmax of the metabolite of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in Tmax of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in Tmax of the metabolite of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in CLr of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in CLr of the metabolite of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in T1/2 of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in T1/2 of the metabolite of dicloxacillin
timeFrame: Day 9 and 27
measure: Change in biomarkers of drug metabolism enzymes and transporters (DMET)
timeFrame: 10 and 28
measure: Change in exosome-derived biomarkers
timeFrame: 10 and 28
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: University of Southern Denmark
state: Region Of Southern Denmark
Study officials:
References: