The Effect of Dicloxacillin on Oral Absorption of Drugs

University of Southern Denmark (SDU)

Status and phase: Completed; Phase 1

Conditions: Healthy Volunteers; Drug-drug Interaction

Treatments: Drug: Dicloxacillin

Study type: Interventional

Funder types: Other

Identifiers

NCT05073627

2021-003814-37 (EudraCT Number)

AKF-400

Details and patient eligibility

About

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.

Enrollment: 12 patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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12 participants in 2 patient groups

Baseline

No Intervention group

Description:

The investigators measure the baseline of dicloxacillin and the probe drug dabigatran etexilate.

Dicloxacillin treatment

Experimental group

Description:

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.

Treatment:

Drug: Dicloxacillin